Cessation of drug use in chronic opiate abusers produces a severe withdrawal syndrome that is highly aversive, and avoidance of withdrawal or associated stimuli is a major factor contributing to opiate abuse. Increased noradrenaline in the brain has long been implicated in opiate withdrawal, but it has not been clear which noradrenergic systems are involved. Here we show that microinjection of beta-noradrenergic-receptor antagonists, or of an alpha2-receptor agonist, into the bed nucleus of the stria terminalis (BNST) in rats markedly attenuates opiate-withdrawal-induced conditioned place aversion. Immunohistochemical studies revealed that numerous BNST-projecting cells in the A1 and A2 noradrenergic cell groups of the caudal medulla were activated during withdrawal. Lesion of these ascending medullary projections also greatly reduced opiate-withdrawal-induced place aversion, whereas lesion of locus coeruleus noradrenergic projections had no effect on opiate-withdrawal behaviour. We conclude that noradrenergic inputs to the BNST from the caudal medulla are critically involved in the aversiveness of opiate withdrawal.

Hyperactivity of brain norepinephrine (NE) systems has long been implicated in mechanisms of opiate withdrawal (OW). However, little is known about where elevated NE may act to promote OW. Here we report that the bed nucleus of the stria terminalis (BNST), the densest NE target in the brain, is critical for NE actions in OW. (1) Many BNST neurons become Fos+ after OW. Pretreatment with the beta antagonist, propranolol, markedly reduces OW symptoms and the number of Fos+ cells in the BNST. (2) Numerous neurons in the nucleus tractus solitarius (A2 neurons) and the A1 cell group are triple labeled for tyrosine hydroxylase, a retrograde tracer from the BNST, and Fos after OW, revealing numerous NE neurons that project to the BNST from the medulla that are stimulated by OW. Fewer such triple-labeled neurons were found in the locus caeruleus. (3) Behavioral studies reveal that local microinjections of selective beta-adrenergic antagonists into the BNST attenuate OW symptoms. In particular, withdrawal-induced place aversion is abolished by bilateral microinjection of a cocktail of selective beta 1 (betaxolol) plus the beta 2 (ICI 181,555) antagonists (1.0 nmol each/0.5 microL per side) into the BNST. Similar results were obtained with neurochemically selective lesions of the ventral ascending NE bundle, the pathway for A1 and A2 projections to the BNST. Similar lesions of the dorsal NE bundle of projections from the locus caeruleus had no effect on either aversive or somatic withdrawal symptoms. Together, these results indicate that beta-receptor activation in the BNST is critical for aversive withdrawal symptoms, and that A1 and A2 neurons in the medulla are the source of this critical NE.

No abstract

No abstract

Using a reinstatement procedure, it has been shown that intermittent footshock stress reliably reinstates extinguished drug-taking behaviour in rats. Here we studied the role of noradrenaline (NE), one of the main brain neurotransmitters involved in responses to stress, in reinstatement of heroin seeking. We first determined the effect of clonidine, an alpha-2 adrenergic receptor agonist that decreases NE cell firing and release, on stress-induced reinstatement of heroin seeking. Rats were trained to self-administer heroin (0.1 mg/kg per infusion, IV, three 3-h sessions per day) for 9-10 days. Extinction sessions were given for up to 11 days during which saline was substituted for the drug. Tests for reinstatement were then conducted after exposure to intermittent footshock (5, 15 and 30 min, 0.5 mA). During testing, clonidine was injected systemically (10-40 microgram/kg, i.p.) or directly into the lateral or fourth ventricles (1-3 microram). Clonidine (1-2 microgram per site) or its charged analogue, 2-[2, 6-diethylphenylamino]-2-imidazole (ST-91, 0.5-1 microgram per site), was also injected bilaterally into the locus coeruleus (LC), the main noradrenergic cell group in the brain. Clonidine blocked stress-induced reinstatement of drug seeking when injected systemically or into the cerebral ventricles. In contrast, neither clonidine nor ST-91 consistently altered stress-induced reinstatement when injected into the locus coeruleus. We therefore studied the effect of lesions of the lateral tegmental NE neurons on stress-induced reinstatement. 6-Hydroxydopamine (6-OHDA) lesions performed after training for heroin self-administration had no effect on extinction of heroin-taking behaviour, but significantly attenuated reinstatement induced by intermittent footshock. These data suggest that: (i) clonidine prevents stress-induced relapse to heroin seeking by its action on neurons other than those of the locus coeruleus; and (ii) activation of the lateral tegmental NE neurons contributes to stress-induced reinstatement of heroin seeking.

Cocaine is believed to exert its psychostimulant effects through activation of the mesocorticolimbic system. Although the nucleus accumbens, in particular, has been hypothesized as the site of action of cocaine's stimulating effects, there is no direct evidence that microinjection of cocaine into this region produces behavioral activation. The present experiments investigated the locomotor response to microinjection of cocaine (0, 10, 30, 100 micrograms/0.5 microliter) into the nucleus accumbens in rats. Cocaine elicited a pronounced, dose-dependent motor activation of approximately 60 min duration. This stimulant effect was blocked by prior administration of a dopamine (DA) receptor antagonist, cis-flupenthixol. The response to cocaine was differentiated from nucleus accumbens microinjections of procaine and lidocaine, compounds that have potent local anesthetic effects but little affinity for the dopamine-uptake site. Neither procaine nor lidocaine (0, 10, 30, 100 micrograms/0.5 microliter) had any overall effect, although activity was somewhat decreased in the initial part of the test session and increased at the end, relative to control activity. Cocaine injected into the anterior dorsal or ventrolateral striatum (100 micrograms) also increased motor activity; procaine and lidocaine had no effect. Cocaine injected into the ventrolateral striatum significantly increased stereotypy. The amplitude of motor activation following cocaine injection into nucleus accumbens was much greater than that elicited at the other striatal sites. Further, observation of the time course of motor activation following cocaine injection into the anterior dorsal and ventrolateral striatum suggested that the motor effect was due to diffusion, most likely to the nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

The mu (mu) opioid receptors, which mediate the effects of morphine, are widely distributed in brain. We have examined the distribution of mRNA encoding a mu opioid receptor in rat brain with in situ hybridization histochemistry at the single-cell level to obtain information about the cell types synthesizing this receptor. Only neurons, not glia, were labeled in discrete brain regions. High levels of labeling were detected in the thalamus, striosomes of the caudate-putamen, globus pallidus, and brain regions involved in nociception, arousal, respiratory control, and, possibly, addiction. The general distribution of the receptor mRNA paralleled that of mu opioid binding sites with some notable exceptions. These include the cerebral cortex, which contains binding sites, but very few labeled neurons. No labeling was observed in the cerebellum, a region devoid of mu binding sites. Three main findings emerged from these experiments: 1) the mRNA was present in regions mediating both the therapeutic (analgesia) and the unwanted (respiratory depression, addiction) effects of morphine, 2) the mRNA was very densely expressed by neurons known to receive dense enkephalin-containing inputs, and 3) the dissociation between the presence of binding sites and absence of mRNA in some brain regions supports a presynaptic localization of mu opioid receptors in these areas. Alternatively, other subtypes of mu opioid receptors may be encoded by a different mRNA. These results provide new insights into the receptor types and neuronal circuits involved in the effects of endogenous opioids and morphine.

No abstract