Gordon T. Pryor

On the role of endogenous opioid peptides: Failure of naloxone to influence shock escape threshold in the rat

Abstract Rats treated with doses of naloxone sufficient to block morphine analgesia showed no change in the threshold for escape from foot shock. The data offer no support to the hypothesis that an endogenous opioid modulates responsiveness to pain and discomfort.

Interactions of Δ9-tetrahydrocannabinol with d-Amphetamine, cocaine, and nicotine in rats ☆ ☆☆

The acute, reciprocal dose-response interactions between delta9-tetrahydrocannabinol (delta9-THC; 2.5, 5.0 and 10.0 mg/kg; IG) and each of three stimulants - d-amphetamine (dA; 1, 2 and 4 mg/kg; IP), cocaine (COC; 10, 20 and 30 mg/kg; IP), and nicotine (NIC; 0.25, 0.5 and 1.0 mg/kg; IP) were studied for their effects on performance of a conditioned avoidance response (CAR), photocell activity, heart rate, body temperature, and rotarod performance. delta9-THC impaired CAR and rotarod performance, depressed photocell activity, and decreased heart rate and body temperature. None of the three stimulants influenced CAR performance, but dA and COC increased the number of intertrial responses, and this latter effect was partially antagonized by delta9-THC. dA and COC, but not NIC, stimulated photocell activity. delta9-THC completely blocked this effect of dA, whereas there was mutual antagonism between delta9-THC and COC on this measure and NIC markedly potentiated the depression caused by delta9-THC. dA and COC tended to offset the impairment of rotarod performance caused by delta9-THC, whereas NIC augmented it. The bradycardia and hypothermia caused by delta9-THC tended to be augmented by these stimulants, especially NIC. The interactions were also studied after subacute treatment for six days with delta9-THC and/or each of the three stimulants. There was evidence for tolerance to the effects of delta9-THC on all measures and this tolerance generally resulted in less interactive effects between delta9-THC and the stimulants. Little or no tolerance was seen for the effects of the three stimulants or their interaction with delta9-THC. The time course of radioactivity derived from 14C-delta9-THC and each of the radiolabelled stimulants was determined in plasma and brain. Only minor interactive effects were found and, in general, they could not account for the functional interactions.

Effects of p-chlorophenylalanine on conditioned avoidance learning

A single injection of p-chlorophenylalanine enhanced the performance of two strains of rats in a conditioned avoidance task. The enhancement was especially evident at low UCS intensities for one strain and at high UCS intensities for the other strain. Chronic p-chlorophenylalanine treatment retarded the performance of rats and mice in conditioned avoidance tasks.

Sensory-evoked potentials in rats chronically exposed to trichloroethylene: Predominant auditory dysfunction

Sensory-evoked potentials (EPs) were studied in male Long-Evans and Fischer-344 rats in order to characterize the electrophysiological consequences of chronic inhalation exposure to trichloroethylene (TCE). Groups of ten Long-Evans rats were exposed to air or 1600 ppm or 3200 ppm TCE for twelve weeks and evaluated periodically with a multisensory test battery. Brainstem auditory-evoked response (BAER) amplitudes were depressed by TCE, whereas somatosensory and visual potentials remained normal. The effects on BAERs, which varied with tone intensity and frequency, suggested that TCE causes a predominantly high-frequency hearing loss. Comparable effects were obtained in both strains of rats and were like those previously observed following exposure to toluene.

Combined effects of solvents on the rat's auditory system: styrene and trichloroethylene

Because exposures to toxic agents typically involve more than one substance, it is necessary to know if combined exposures pose different risks than those to single agents. Many solvents have been implicated in central nervous disorders and some of them are known to produce hearing loss, probably mediated by damage to cochlear hair cells. Hearing loss was studied by recording the brainstem auditory evoked response (BAER) in male Long Evans rats exposed 8 h/day for 5 days to mixtures of styrene (STY) and trichloroethylene (TCE). Dose groups included air or solvent pairs (STY/TCE) in the following concentrations (ppm): (0:3000), (250:2250), (500:1500), (750:750) and (1000:0). Decreased BAER amplitude, indicative of hearing loss, was correlated with blood levels of total solvent. The effects were as predicted by a linear dose-addition model, indicating neither synergistic nor antagonistic interactions at the concentrations studied.

Interactions between Δ9-Tetrahydrocannabinol and phencyclidine hydrochloride in rats☆☆☆★

delta9-Tetrahydrocannabinol (THC; 2.5, 5.0, 10.0 mg/kg, PO) impaired avoidance and rotarod performance, and caused bradycardia and hypothermia. Phencyclidine (PCP; 1.25, 2.5, 5.0 mg/kg, IP) impaired avoidance and rotarod performance and caused a marked increase in photocell activity. When combined, the depressant properties of each drug were enhanced and the stimulation of photocell activity cg/kg THC and its interactions with PCP followed subacute treatment for six days, whereas many of the effects of PCP were enhanced after subacute treatment with a dose of 2.5 mg/kg. Open-field behavior was affected by each drug alone and in combination in a similar way as photocell activity, but the depression caused by their interaction was greater; both drugs caused an increase in urination. Response rates on an FR-10 schedule of food reinforcement were decreased by 2.5 mg/kg PCP, but not by 5.0 mg/kg THC; the combination caused greater response suppression than either drug alone. The functional interactions between THC and PCP were not related to changes in the concentrations of 14C or 3H in plasma or brain derived from 14C-delta9-THC and 3H-PCP, respectively.

A toluene-induced motor syndrome in rats resembling that seen in some human solvent abusers.

The purpose of these experiments was to determine the extent to which subchronic exposure of rats to toluene might cause symptoms similar to those seen in some heavy abusers of toluene-containing products. In the first exploratory experiment, weanling male Fischer-344 rats were exposed to air, toluene, n-hexane, or a mixture of toluene, n-hexane, and methyl ethyl ketone (8 h per day, 7 days per week) for 11 weeks. A mild peripheral neuropathy was revealed by measures of grip strength in the rats exposed to n-hexane alone or in the mixture, but not in the rats exposed to toluene. Instead, the rats exposed to toluene alone developed a persisting motor syndrome characterized by a shortened and widened gait and a widened landing foot splay. The rats exposed to toluene alone or in the mixture were also hearing impaired, but not the rats exposed to n-hexane alone. In the second experiment, done to confirm and extend these results, weanling male Fischer-344 rats were exposed to toluene under three different daily schedules--2,200 ppm continuously for 8 h per day; 4,400 ppm, 30 min each h, 8 h per day; or 6,200 ppm, 15 min each h, 8 h per day. The exposures were 7 days per week for 23 weeks. The motor syndrome and hearing impairment were replicated in all essential respects in all toluene-exposed groups with no appreciable differences attributable to the daily exposure schedules. The effects were still evident 15 weeks after the last exposure. Toluene inhibited weight gain in both experiments, and in the second experiment, it was found that skeletal growth (torso length, rump width) was also inhibited. Toluene did not significantly impair rotorod performance in either experiment or acquisition of a spatial-navigation task in the second experiment. No neuropathologic correlates of the persisting motor syndrome were found in either experiment when the rats were sacrificed 9 and 16 weeks after the last exposure, respectively. These results demonstrate that toluene can cause a persisting motor syndrome in rats that resembles, to some extent at least (i.e., wide-based ataxic gait), the syndrome seen in some heavy abusers of toluene-containing products.

The hearing loss associated with exposure to toluene is not caused by a metabolite.

Exposure to toluene causes a marked hearing loss in rats, and this effect has been observed in some human solvent abusers. The issue of whether toluene or one of its metabolites is responsible for this effect has not been examined. To attempt to resolve this issue, we manipulated the metabolism, and thus the circulating levels, of toluene as follows. Two groups of rats were exposed to phenobarbital (PB) in their drinking water (0.1%) for seven days to induce detoxifying liver enzymes; two other groups had access to PB-free water. Then half of the rats exposed to PB or water were exposed to filtered air or a concentration of toluene expected to cause hearing loss. Levels of toluene in blood were markedly reduced by the PB and the excretion of hippuric acid was increased. All rats were tested for auditory sensitivity by brainstem auditory-evoked response (BAER) audiometry using a 16-kHz tone pip. The rats exposed to toluene alone showed a marked reduction in the integrated BAER waveform, indicative of the expected hearing deficit. None of the other treated rats showed any deviation from controls (i.e., water and air). These results provide strong evidence that toluene itself is responsible for the auditory dysfunction. Toluene also caused the rats to increase their fluid consumption and urine output; these effects were not altered by PB. Identification of toluene as the proximal ototoxicant should facilitate the search for the mechanism of this effect.

Combined effects of paired solvents on the rat's auditory system

A number of volatile organic solvents have been shown to be ototoxic to rats, but there is little information regarding how solvents might act in this way when encountered in combination. To examine this issue, male Long Evans rats were exposed by inhalation to pairs of solvents known to be ototoxic when administered individually; those reported on here are trichloroethylene+toluene, mixed xylenes+trichloroethylene, xylenes+chlorobenzene, and chlorobenzene+toluene. Rats were exposed 8 h/day for 5 consecutive days, using complementary proportions of isoeffective concentrations of the solvents alone. Hearing was assessed by brainstem-evoked response audiometry. The effects were as predicted by a linear dose-addition model, indicating additive rather than synergistic or antagonistic interactions at the concentrations studied.

Multimodal effects of acute exposure to toluene evidenced by sensory-evoked potentials from fischer-344 rats

Male Fischer-344 rats were exposed by inhalation to 500, 2000, 5000, 8000 and 16000 ppm toluene for 30 min in two experiments. Exposures up to 8000 ppm in Experiment 1 caused concentration-related changes in the click-elicited brainstem auditory-evoked response (CBAER), flash-evoked potential (FEP) and somatosensory-evoked potential (SEP). Latencies of CBAER components were prolonged and amplitudes of late components were increased by toluene. Toluene did not detectably alter the latencies of FEP or SEP components. Early FEP component-amplitudes were increased and late component-amplitudes were decreased; toluene also induced a poststimulus oscillation in the FEP. Most component-amplitudes of the SEP were substantially increased, but N2P2 amplitude appeared to be more sensitive than other components to depressant effects of the solvent. The same effects on the CBAER were observed in Experiment 2, but a more substantial increase in the amplitudes of late components elicited by tone pips suggested that frequency-dependent cochlear irritation might underlie previously observed subchronic ototoxicity. These effects were increased by exposure to 16000 ppm toluene. Effects like those observed in Experiment 1 were noted on the FEP, but the oscillations were less with exposure to 16000 than 8000 ppm. Changes in the SEP were evident within 2 minutes of exposure onset, and amplitudes increased over the course of about 15 min, leveling off or decreasing thereafter. The amplitude of the N2P2 component was again less influenced than other components during exposure to 8000 ppm and was reduced to less than baseline amplitude by 16000 ppm. Effects of concentration and rates of development and recovery were systematically related to SEP component latency. Toluene appears to have both enhancing and inhibiting effects on neural pathways serving sensory systems, depending on the modality and the site of generation of the components within modalities. A particular balance between these properties might relate to the hedonic characteristics of this abused solvent.