Patterns of service use and treatment involvement of methadone maintenance patients.

Although methadone maintenance is an effective treatment for opiate addiction, variations in treatment outcome are evident. These variations may be explained in part by the rehabilitative experiences of patients as reflected in their use of collateral services. This study examined service involvement of 409 methadone maintenance patients at four clinics in order to identify the types of services used and the extent to which potentially rehabilitative services were used. Aside from welfare, there was a strikingly low level of service utilization. Even when services were used, the levels of this use were so low as to be virtually ineffective. These findings regarding treatment and social service utilization suggest that there may not be any attempt to match service provision with patient needs for services. A more rational approach to matching patient needs and available services is thus called for.

Discriminative stimulus effects and receptor binding of enantiomeric pairs of cannabinoids in rats and pigeons; a comparison.

The cannabimimetic activity of two enantiomeric pairs of compounds structurally different from the classical cannabinoids was evaluated in rats and pigeons, trained to discriminate between the presence and absence of (-)-delta-9-tetrahydrocannabinol (THC). One pair of enantiomers [compounds (+)-HU-249 and (-)-HU-250] has a 5-membered oxygen-containing benzofuran ring; the second pair [(+)-HU-253 and (-)-HU-254] does not have an oxygen-containing ring. The onset of cannabimimetic activity was slower, and duration of action was longer for the test compounds than for THC. HU-250 exhibited cannabimimetic activity with a potency similar to THC in both species; HU-249 was 22 times less active than THC. The pattern of response rate and THC-like responding obtained with HU-249 were dissociated; THC-like responding occurred during the later test intervals when suppression of response rate was reduced. HU-250 bound to the cannabinoid receptor with a Ki of 47.6 nM, essentially identical to that of THC. HU-249 was much less active, with a Ki of 28.3 microM. The triacetate enantiomers, HU-253 and HU-254, occasioned THC-like responding in both species, HU-254 being about 4.5 times less potent than THC and 3 to 4 times more potent than HU-253. In binding, HU-253 was also less potent than HU-254. The corresponding triols were considerably more potent than the acetates; (-)-HU-256 had a Ki of 198 nM, whereas (+)-HU-255 had a Ki of 43.8 nM, comparable to that of THC.

Quantal vs. graded generalization in drug discrimination: measuring a graded response.

In drug discrimination research, detection of drug stimuli by animals is used for investigating various properties of psychoactive drugs. The major issue addressed by this paper is whether detection of drug stimuli by animals is a quantal or graded event. Some data suggest that detection of a drug stimulus by animals is quantal in nature. Thus, variations in drug stimulus substitution may only reflect variations in threshold for detecting the training stimulus rather than the current concept of these data reflecting graded responding to stimulus intensity. Therefore, drug discrimination procedures may have limited utility for detecting quantitative differences in the subjective effects of varying drug doses. In order to examine this problem, a method for measuring continuous response gradients in individual animals is needed. Tests for quantal responding generally use the distribution of responses on two manipulanda as the dependent measure. However, this variable may be inadequate for detecting a graded response, and may actually reflect loss of stimulus control or a deterioration in performance, rather than changes in response magnitude. Most alternative measures utilize response rate. Unfortunately, these measures are influenced by the direct rate-altering properties of some drugs. One possible alternative method is conditioned taste aversion as the discriminative task. This paradigm provides a means for not only ascertaining if graded discriminative responses occur in individual animals, but also more rapidly training a drug discrimination. Thus, using conditioned taste aversion techniques for measuring a drug discrimination may provide better indices for detecting response gradations.

Animal models of drug withdrawal symptoms.

There have been few attempts to model subjective symptoms of drug withdrawal using animals as subjects. Two approaches for developing such models are reviewed. First, using drug discrimination methodology, it may be possible to train animals to detect the effects of withdrawal. This method has two difficulties: 1) the only discriminations trained to date involve precipitated withdrawal, and 2) the stimulus controlling behavior is difficult to specify. Second, withdrawal from many drugs of abuse produces the symptom of anxiety, and it seems likely that animal models of anxiety could be useful for studying drug withdrawal. This hypothesis has been explored most fully using subjects trained to detect the discriminative stimulus properties of the putative anxiogenic drug pentylenetetrazole (PTZ). Withdrawal from benzodiazepines or ethanol substitutes fully for PTZ, and withdrawal from cocaine, morphine, and nicotine substitutes partially for PTZ. Emerging data suggest that other animal models of anxiety may also be useful for detecting drug withdrawal. The final portion of this review examines a behavioral test that is very sensitive for detecting physical signs of withdrawal in animals. In subjects maintained on an operant baseline using food as a reinforcer, withdrawal from a drug of dependence frequently is associated with disruption of that operant behavior. For example, tetrahydrocannabinol and cocaine, drugs that are not traditionally seen as having significant withdrawal signs, produce disruption of operant responding when high-dose administration is terminated, and their readministration reverses this behavioral disruption. Based on the observation that withdrawal is associated with anxiogenic stimuli, we suggest a method to determine if disruption of operant behavior may be related to these stimuli.

Withdrawal from diazepam substitutes for the discriminative stimulus properties of pentylenetetrazol.

Rats were trained to discriminate pentylenetetrazol (PTZ, an anxiogenic drug), 20.0 mg/kg, from saline using a food-maintained two-lever-choice task. When treated chronically with diazepam (DZP) and tested with the benzodiazepine-receptor antagonist Ro 15-1788, withdrawal from DZP produced a PTZ-like stimulus in these subjects that was related directly to the dose of DZP given every 8 hr for 6 days. In contrast, only the highest dose of DZP (80 mg/kg/8 hr) given chronically produced even minimal physical signs of precipitated abstinence after Ro 15-1788. In a separate experiment, Ro 15-1788 produced a PTZ-like stimulus when given at 2-day intervals during chronic administration of DZP. In this experiment, rats were maintained on DZP, 40.0 mg/kg/6 hr for 14 days. These subjects were tested with Ro 15-1788, 40.0 mg/kg, every 2 days during days 6 through 14 of chronic DZP, and Ro 15-1788 substituted for PTZ on 4 of these 5 tests. Because these experiments involved periods of nontraining on the discrimination task, a final experiment was performed to test the stability of stimulus control in rats trained to detect PTZ. DZP was administered for up to 20 days, withdrawal was precipitated by Ro 15-1788 and after an additional 16 to 40 days of nontraining, stimulus control was tested. There was no significant decline in stimulus control over this period. These results suggest that PTZ discrimination provides a sensitive, stable assay for the detection of withdrawal from benzodiazepine dependence.

Quantal detection and homogeneous sensitivity in a pentylenetetrazol discrimination.

Rats were trained to discriminate pentylenetetrazol (PTZ, 20 mg/kg) from saline in a two-lever operant task. Correct lever presses were reinforced with food under the control of a fixed ratio 10 schedule. In tests of the effect of PTZ dose on lever selection, rats selected the PTZ lever in a dose-dependent manner, with peak latency at the approximate ED50 dose (10 mg/kg). Rats usually pressed only the selected lever, regardless of dose, indicating that lever selection was a quantal (or bimodal) function of stimulus intensity. Lever biases observed during training sessions did not predict the performance of individual rats in tests with the ED50 dose. In three independent trials with this intermediate dosage, the rats selecting the PTZ lever varied from trial to trial, suggesting that rats detecting this dose did not form a stable subgroup. The pattern of lever selections across these three trials was not significantly different from that predicted by a model in which all subjects shared the same probability for detecting the drug stimulus. These results demonstrate that lever selection in a two-lever drug-discrimination task can be quantal in nature, and suggest that rats trained with PTZ, 20 mg/kg, are homogeneous in sensitivity to this stimulus.

Enhancement of a diazepam withdrawal symptom by bicuculline and yohimbine.

The role of the GABA system in producing a pentylenetetrazol-like interoceptive discriminative stimulus during withdrawal from diazepam was investigated in rats by determining the sensitivity of this system to GABAergic drugs before and after chronic treatment with diazepam. Food-restricted rats were trained to obtain a reward of food by responding on one lever following an injection of pentylenetetrazol (PTZ; 20 mg/kg) and the other lever following an injection of saline (1 ml/kg). After rats had acquired this discrimination, the effectiveness of Ro 15-1788, bicuculline and yohimbine to substitute for pentylenetetrazol was determined. Prior to chronic treatment with diazepam, rats selected the appropriate lever for saline after Ro 15-1788 and the appropriate lever for pentylenetetrazol after bicuculline (0.04-2.5 mg/kg) or yohimbine (0.16-5.0 mg/kg). Although the selection of the appropriate lever for pentylenetetrazol was dose-dependent, full substitution for pentylenetetrazol was not obtained with either drug as larger doses of bicuculline produced convulsions while the rats began to select the appropriate lever for saline after larger doses of yohimbine (bell-shaped curve). Diazepam blocked the pentylenetetrazol-like interoceptive discriminative stimulus for bicuculline. The rats were then injected with diazepam (80 mg/kg/8 hr) for 24 days. Upon termination of the administration of diazepam, the animals were tested for lever-selection following the administration of saline, Ro 15-1788 (10 mg/kg), bicuculline (0.32, 0.64 and 1.25 mg/kg) or yohimbine (0.16, 0.64 and 2.5 mg/kg). After saline, 33% of the rats selected the appropriate lever for pentylenetetrazol whereas selection of this lever was enhanced after Ro 15-1788, bicuculline or yohimbine.(ABSTRACT TRUNCATED AT 250 WORDS)