Rat brain sites responsive to etorphine: analgesia and catatonia.

One hundred forty-two rats given intracerebral microinjections of 1 microgram of etorphine hydrochloride were observed for subsequent analgesia (flinch-jump technique) and catatonia (bar test). Neuroanatomical specificity of effect was demonstrated to the extent that behavioral effects did not result from injections into areas of low opiate receptor binding affinity, such as medial cerebral cortex and hippocampus, nor were positive results obtained from injections into fiber bundles, such as the corpus callosum and internal capsule. Positive results were obtained in a large number of areas, ranging from brain stem to telencephalon. Injections eliciting analgesia without catatonia were limited in number (9 animals) and were widely scattered throughout neuroanatomical loci. Microinjection more frequently elicited catatonia only (29 animals), and site of injection was limited to posterior cerebral cortex, posterior amygdala, dorsal reticular formation, and cerebral aqueduct. Dual behavioral effects were elicited in 28 of the animals and occurred most frequently upon injection into the periaqueductal gray, inferior colliculus, and cerebral aqueduct. (Injection into cerebral aqueduct produced 50% catatonia only and 50% dual effects). The study suggests that opiate-elicited analgesia and catatonia may be neuroanatomically distinct phenomena.

Shuttlebox self-stimulation in the rat: an anatomical analysis and the effect of morphine with two current levels.

A shuttlebox paradigm was used to train rats to turn electrical stimulation ON and OFF by crossing back and forth in a stabilimeter cage. Two experiments are presented. In the first experiment a threshold current level was used in testing four electrode sites: the lateral hypothalamic area (LHA), lateral septal nucleus (LSN), periaqueductal grey (PAG), and the mesencephalic reticular formation (MRF). In the second experiment, a suprathreshold current level was used to explore two electrode sites: the PAG and the MRF. Stimulation with electrodes in the MRF produced an aversive behavioral response; animals shuttled mainly to turn electrical stimulation OFF. At the other electrode sites, both rewarding and aversive properties were apparent: animals shuttled to turn the stimulation ON as well as OFF. Systemic morphine (10 mg/kg) injections nonselectively increased both average ON and OFF times for the three rewarding sites (minimum p less than 0.05) at the threshold current level. Systemic morphine injections (10 mg/kg) in animals stimulated at a suprathreshold current level in the PAG selectively increased time spent with stimulation ON (p less than 0.05) as opposed to time spent with stimulation OFF. No significant behavioral change due to morphine was seen in the aversive MRF at either current level. Animal behavior also was found to vary as a function of site of stimulation (p less than 0.05). The use of suprathreshold currents appears necessary to produce selective reward facilitation effects of morphine such as those found in the PAG or LHA.

Reversal of morphine-induced catalepsy by naloxone microinjections into brain regions with high opiate receptor binding: a preliminary report.

The relationship between opiate binding density and morphine-induced catalepsy was estimated via dose-response analysis of the brain sites in which naloxone microinjections reversed the catalepsy induced by intraperitoneal morphine. One-hundred forty-one experimentally naive male Long-Evans rats were implanted with chemical microinjection guide cannulae aimed for various high-to-moderate binding density areas within caudate nucleus, central gray matter, thalamus, hypothalamus, amygdala, and frontal cortex as well as low density sites in pyriform cortex and various fiber tracts. Overall, 48 out of 91 animals microinjected with naloxone in brain sites having high-to-moderate density of opiate binding showed reversal of the cataleptic response. Dose-response effects were found in all 6 high-to-moderate density sites: ranging from 85% reversals at 100 mcg naloxone over all sites to 34% reversals at 0.01 mcg naloxone. There were no reversals out of 38 naloxone microinjection in brain sites having a low density of opiate binding and no reversals out of 18 saline microinjections in either high-to-moderate or low opiate binding density loci. These results suggest a role for limbic and basal ganglia portions of the opiate system in a motor aspect of narcotic action. We speculate that these loci may also play a role in the motor expression of the response to the analgesic and euphoric actions of morphine to supplement actions mediated through periventricular structures.

Naloxone and shuttlebox self-stimulation in the rat.

Rats self timed electrical brain stimulation on and off periods in a shuttlebox. Electrodes for self-stimulation were located either in the lateral hypothalamic area (LHA) or the periaqueductal gray (PAG). Doses of the narcotic antagonist, naloxone, were administered intraperitoneally immediately prior to self-stimulation testing. Doses of 1.0, 5.0, 10.0 or 50.0 mg/kg failed to alter shuttlebox self-stimulation behavior. These results are inconsistent with one lever-press self-stimulation study employing PAG electrodes [3], but agree with other studies using LHA electrodes [9, 15, 21, 24). Possible reasons for the discrepancy are suggested.

Naloxone reversal of morphine catationia: role of caudate and periaqueductal gray.

The narcotic antagonist, naloxone, was microinjected into the head of the caudate nucleus (HC), periaqueductal gray matter (PG), and cerebellar white matter (CB) of rats to counteract the catatonia induced by systemic morphine. Naloxone produced a loss of the catatonic response when administered into HC or PG, but not when microinjected into CB. Isotonic saline in HC, PG, and CB did not counteract the catatonic effects of morphine. The reversal of catatonia was similar for naloxone injections in HC and PG. Both these areas have high concentrations of opiate receptors while CB has few opiate receptors. It is suggested that the HC and PG are involved in the reversal of the catatonic effects of morphine via the high concentrations of opiate receptors found there.

Morphine and shuttlebox self-stimulation in the rat: tolerance studies.

Rats were trained to turn lateral hypothalamic electrical brain stimulation on and off by crossing back and forth in a shuttlebox. Injections of 10 mg/kg morphine doubled the amount of time animals left the stimulation ON without altering OFF times. Tolerance did not develop to this action during 5 daily trials. Injections of 20 mg/kg produced a 4- to 5-fold increase in average ON times together with a large increase in average OFF times. Tolerance did not develop to the ON time increase over 5 daily injections, but did partially develop to the OFF time increase. The ON time increase appears to be based on a mechanism separate from the analgesic action of morphine and from the OFF time increase. Differentiable neurological structures and receptor systems may mediate these actions.

Etorphine and shuttle-box self-stimulation in the rat.

Rats were trained to turn rewarding electrical brain stimulation on and off by crossing back and forth in a shuttle-box. Moderate doses of the narcotic analgesic, etorphine, increased mean ON times while having little effect on OFF times. Tolerance did not develop to the reward enhancement action over five consecutive days of injections. This paradigm seems valuable for exploration of the reinforcing properties of narcotic drugs.

Morphine and shuttle-box self-stimulation in the rat: a model for euphoria.

In a shuttle-box self-stimulation paradigm, analgesic doses of morphine increase the amount of time a rat leaves rewarding brain stimulation on, without altering average OFF times. This paradigm may serve as a model for the euphoria induced by narcotic drugs and as a useful tool for evaluating the reinforcing effects of drugs.

Neural activity changes correlated with central anticholinergic blockade of cholinergically-induced drinking.

In the rat, microinjections of carbachol into the septal area elicited water ingestion and increased multiple unit activity at this site and also the noninjected lateral hypothalamus. Carbachol injection into the lateral hypothalamus also elicited water ingestion, but multiple unit activity did not increase in this structure, although it did in the noninjected septal area. If carbachol was injected into one of these sites and isotonic saline into the other (conditions comparable to those for which drinking has been previously demonstrated), increased multiple unit activity was still found. However, if carbachol was injected into one of these sites and atropine into the other (conditions comparable to those for which the blockade of drinking has been previously demonstrated), the increases in multiple unit activity were blocked. Carbachol-elicited drinking may result from neural activity changes similar to those recorded in this study, and atropine may inhibit carbachol-elicited drinking by inhibiting such neural firing changes.