Changes In Regional Cerebral Glucose Utilization Research Articles

Is morphine dependence mediated exclusively by the Mu receptor?

Regional cerebral glucose utilization (RCGU) and behavior during naloxone precipitated withdrawal were studied in rats made dependent on either sufentanil, a highly selective mu opiate agonist, or morphine. Changes in RCGU during withdrawal in 23 of 24 anatomically related limbic and brainstem structures were indistinguishable between rats dependent on morphine or sufentanil. Linear regression analysis indicated that RCGU changes during withdrawal in these two groups were highly correlated (r = 0.95). Withdrawal behaviors (autonomic signs of withdrawal, jumps, weight loss, and incidence of diarrhea) were likewise indistinguishable between the two groups. The correlations of both these measurements of dependence suggest that chronic occupation of mu opiate receptors alone is sufficient to produce dependence that is indistinguishable from morphine dependence.

Dependence and withdrawal following intracerebroventricular and systemic morphine administration: functional anatomy and behavior

Regional cerebral glucose utilization (RCGU) and behavior during precipitated morphine withdrawal were studied in rats made dependent by either intracerebroventricular (i.c.v.) or subcutaneous (s.c.) administration of morphine. [4C]2-deoxy-d-glucose autoradiography revealed that RCGU increased in an anatomically related group of limbic and brainstem structures in rats that were in morphine withdrawal precipitated by naloxone administration compared to morphine-dependent controls that were not in precipitated withdrawal. Correlation of RCGU for 24 brain structures comparing i.c.v. vs s.c. morphine-treated rats was highly significant for groups in withdrawal and for controls (r values, 0.958 and 0.971, respectively). Withdrawal behaviors including autonomic signs of withdrawal, withdrawal jumping, and incidence of diarrhea were not different between the two groups in withdrawal (i.c.v. and s.c.). Weight loss during withdrawal increased (P < 0.05) in rats made dependent by s.c. morphine administration compared to rats that received morphine by the i.c.v. route. Taken together, these results indicate that RCGU changes during morphine withdrawal result solely from effects of chronic morphine in the central nervous system, not in peripheral sites. The increased weight loss of s.c.-treated, morphine-dependent rats in withdrawal suggests an independent peripheral effect perhaps mediated by visceral opiate receptors.

The effects of l-DOPA on regional cerebral glucose utilization in rats with unilateral lesions of the substantia nigra

Using [ 14C]2-deoxyglucose autoradiography, we have studied the effects of systemically administered l-DOPA (10, 25 and 50 mg/kg s.c.) on regional cerebral glucose utilization (RCGU) in rats with unilateral substantia nigra lesions. In comparison with lesioned rats treated with saline, the lesioned-DOPA treated rats demonstrated contralateral turning and RCGU changes in both ipsilateral and contralateral brain regions. l-DOPA treatment markedly increased RCGU in the ipsilateral entopeduncular nucleus (EP) and substantia nigra pars reticulata (SNr), cell groups that receive direct striatal input and function as major outflow pathways of corpus striatal activity. In contrast, l-DOPA did not alter RCGU in the globus pallidus (GP), supporting the thesis that dopamine (DA) has different effects on striatal outflow to the GP compared with outflow to both the EP and SNr. Moderate RCGU increases were observed in the ipsilateral subthalamic nucleus (STN), lateral midbrain reticular formation (LMRF), and deep layers of the superior colliculus (DLSC), all regions which receive direct projections from the GP, EP or SNr. l-DOPA decreased RCGU in the ipsilateral lateral habenular nucleus (LHN) and increased RCGU in the contralateral LHN, changes that we suggest are mediated via altered neuronal activity in the striatum and EP. The results suggest that systemically administered l-DOPA, after conversion to DA in the brain, interacts with supersensitive DA receptors in the DA-depleted striatum to selectively activate efferent pathways. Furthermore, the data suggest that the LMRF and DLSC are functionally activated during l-DOPA induced turning and support the hypothesis that nigroreticular and nigrocollicular projections are of physiologic significance in the expression of striatal activity.

Dose effects of naloxone on fixed morphine dependence: simultaneous behavioral and 2-deoxyglucose study in the rat

We have simultaneously studied regional cerebral glucose utilization (RCGU) and behavior during naloxone precipitated morphine withdrawal. For RCGU studies, 25 brain regions were analyzed that previously had been shown to participate in morphine withdrawal. Four established behavioral signs of morphine withdrawal were recorded: wet shakes, jumping, weight loss, and autonomic signs. Using a 10 4 range of naloxone dose (0.0005–5.0 mg/kg), dose dependent effects were found for 3 behaviors: jumping, weight loss and autonomic signs. The incidence of wet shakes did not correlate with naloxone dose. Increases in RCGU in several specific brain sites were also naloxone dose dependent. Naloxone dose dependent increases in RCGU during precipitated morphine withdrawal may be divided into 3 classes of responses: Class I structures (paraventricular, ventromedial, and lateral hypothalamus) exhibited their largest RCGU increases between 0.005 and 0.05 mg/kg of naloxone; Class II structures (preoptic areas, basal ganglia, anterior and intralaminar thalamic nuclei, mammillary nuclei, and certain midbrain regions) showed gradual RCGU increases across the 10 4 range of naloxone dose; and, Class III structures (diagonal band, medial and lateral septum, and the central amygdaloid nucleus) displayed large RCGU increases across 0.5–5.0 mg/kg of naloxone. Regression analysis of RCGU vs behavior showed correlations between Class I responses and autonomic signs ( p<0.010); weight loss was correlated with all 3 classes of naloxone dose dependent RCGU responses during withdrawal ( p<0.05). The strong positive correlation among these RCGU increases and certain morphine withdrawal behaviors supported the use of RCGU measurements in specific brain sites as a sensitive and objective biochemical indicator of the presence and severity of morphine dependence. In addition, this study demonstrates the changes in RCGU in different brain regions are heterogeneous with respect to naloxone dose and appear reproducibly along a continuum from mild to severe withdrawal.

Effects of dopaminergic stimulation on functional brain metabolism in rats with unilateral substantia nigra lesions

We have studied regional cerebral glucose utilization (RCGU) in awake, unrestrained rats 21 days after unilateral substantia nigra lesions following treatment with either apomorphine (0.5 mg/kg s.c.) or d-amphetamine (2.5 mg/kg s.c.). In ‘control’ rats with a unilateral SN lesion, there was a 30–40% increase in RCGU in the ipsilateral globus pallidus (GP) and a 15–25% increase in the ipsilateral lateral habenular nucleus (LH). Apomorphine treatment produced contralateral while d-amphetamine elicited ipsilateral turning in the lesioned rats. Apomorphine administration led to an increase in RCGU in the ipsilateral striatum, entopeduncularis (EP), and substantia nigra pars reticulata (SNPR); while d-amphetamine elicited similar changes in the same structures contralateral to the lesion. Both apomorphine and d-amphetamine treatment led to bilateral increases in RCGU in the subthalamic nuclei. The increased RCGU found in the ipsilateral GP in ‘lesioned controls’ was reduced to control levels by apomorphine administration, while amphetamine treatment increased RCGU in the contralateral GP without affecting glucose utilization in the ipsilateral GP. Furthermore, apomorphine treatment markedly reduced RCGU in the LHN bilaterally while amphetamine reduced RCGU only in the contralateral LHN. The effects of apomorphine were dose-dependent. Haloperidol (1 mg/kg s.c.) pretreatment completely blocked the development of asymmetric changes in RCGU in nigral lesioned rats after apomorphine administration. These results suggest that apomorphine, a direct dopamine agonist, selectively activated basal ganglia pathways ipsilateral to substantia nigra lesion by interacting with supersensitive dopamine receptors in the ipsilateral striatum. In contrast, d-amphetamine, an indirect dopamine agonist, selectively activated pathways in the contralateral basal ganglia by releasing endogenous dopamine from the intact nigrostriatal pathway. Furthermore, the data suggest that striatal efferents to the GP are not controlled in the same manner as efferents to the EP and SNPR. Finally, these asymmetric changes in RCGU in basal ganglia structures produced by apomorphine or d-amphetamine do not appear to be a consequence of the turning behavior, but rather appear to be proximate effects of the drugs administered.