Coadministration of -opioid receptor agonists ( -agonists) with cocaine prevents alterations in dialysate dopamine (DA) concentration in the nucleus accumbens (Acb) that occur during abstinence from repeated cocaine treatment. Quantitative microdialysis was used to determine the mechanism producing these effects. Rats were injected with cocaine (20 mg/kg, i.p.), or saline, and the selective -agonist U-69593 (0.32 mg/kg, s.c.), or vehicle, once daily for 5 d. Extracellular DA concentration (DA ext ) and extraction fraction (E d ), an indirect measure of DA uptake, were determined 3 d later. Repeated cocaine treatment increased E d , whereas repeated U-69593 treatment decreased E d , relative to controls. Coadministration of both drugs yielded intermediate E d values not different from controls. In vitro DA uptake assays confirmed that repeated U-69593 treatment produces a doserelated, region-specific decrease in DA uptake and showed that acute U-69593 administration increases DA uptake in a norbinaltorphimine reversible manner. Repeated U-69593 also led to a decrease in [ 125 I]RTI-55 binding to the DA transporter (DAT), but did not decrease total DAT protein. These results demonstrate that -opioid receptor activation modulates DA uptake in the Acb in a manner opposite to that of cocaine: repeated U-69593 administration decreases the basal rate of DA uptake, and acute U-69593 administration transiently increases DA uptake. -agonist treatment also alters DAT function. The action of -agonists on DA uptake or DAT binding, or both, may be the mechanism(s) mediating the previously reported "cocaineantagonist" effect of -opioid receptor agonists.

In an infant rhesus monkey brain damage resulted from subcutaneously administered monosodium glutamate. Although a relatively high dose of monosodium glutamate was used, the infant was asymptomatic for a 3-hour observation period during which time hypothalamic neurons were undergoing a process of acute cell death. With the electron microscope it was observed that dendrites and cell bodies of neurons are the tissue components primarily affected in brain damage induced by monosodium glutamate.

Anatomical studies employing the immu- MATERIALS AND METHODS Four adult rhesus monkeys (Macaca mulatta) were used for this study. Four weeks prior to experimentation they were anesthetized with phencyclidine (2 mg/kg) and the right external carotid artery was ligated at its origin to facilitate the injection of '50-labeled water into the internal carotid artery. At the same time, three of the monkeys underwent bilateral superior cervical ganglionectomies. The tissue removed was examined histologically to confirm its identity as sympathetic ganglion.In order to administer drugs that might directly affect the central noradrenergic system, two cannulae systems were stereotaxically implanted 3 weeks prior to experimentation under phencyclidine anesthesia (2 mg/kg). Twenty-three gauge stainless steel permanent guide cannulae were placed in each lateral ventricle in all four animals. These cannulae served to administer drugs intended to affect noradrenergic fibers or terminals. In two of the monkeys (both ganglionectomized) a second set set of guide cannulae was bilaterally implanted in a position directly dorsal to the rostral third of the locus coeruleus. These guide cannulae permitted the placement of 30-gauge injection cannulae at the time of the experiment which extended below the tip of the guide cannulae into the locus coeruleus.At the time of the experiment the monkeys were anesthetized with phencyclidine (2 mg/kg), paralyzed with gallamine, and passively ventilated on 100% oxygen. The end-tidal CO2 pressure (PCo2), arterial blood pressure, and rectal temperature were continuously monitored. Rectal temperature was maintained between 370 and 390 with a heating pad. Arterial pH, and arterial CO2 and 02 pressure (Paco2, and PaO2, respectively) were measured before and after each series of isotope injections.The time course of '50-labeled water through the brain was detected by a 3 X 2 inch sodium iodide, thallium-impregnated scintillation detector appropriately positioned and collimated to insure uniform detection efficiency. The signal from the detector was processed in a manner previously described (4). Radioactive water labeled with l5O (half-life 123 sec) was produced for these studies in the Washington University Medical School Cyclotron by deuteron bombardment of nitrogen gas (5).The extraction fraction of labeled water (E) was obtained by graphically extrapolating the 25-60 sec nearly linear interval of the semilogarithmic plot of tissue water clearance (B, Fig. 1) back to the abscissa of the maximum perfusion peak (A, Fig. 1) and computing the ratio E = B/A.Mean CBF was determined by the height/area residue detection method from the injected bolus of labeled water (4,6). This method requires monitoring of the brain residue 3726

No abstract

No abstract

No abstract

No abstract

No abstract