Abraham Wikler

Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats

Summary1.For 6-week periods in two studies, rats made tolerant to and maintained on intraperitoneal injection of morphine (200 mg/kg) once daily in the morning resided on alternate nights in one end of a 3-compartment linear maze with water for drinking and on the intervening nights in the other end-compartment with etonitazene (10 meg/ml) for drinking. On this schedule, temporal contiguity was provided between the unrelieved nocturnal “primary” morphine abstinence syndrome (including elevated frequency of “wet dog” shakes) and the specific environment of the water-end of the linear maze, while in the other end, opportunity was provided for reinforcement of etonitazene-drinking through reduction of the nocturnal “primary” morphine abstinence syndrome. Saline-injected normal rats were trained identically except that the concentration of etonitazene was 5 meg/ml. In one study, the etonitazene solution was tagged with anise-flavor while in the other study, tactile-visual cues were used. Also, other morphine-tolerant and normal rats were maintained on intraperitoneal injections of morphine (200mg/ kg) or saline respectively once each morning for 6 weeks in home cages without any training.2.At the end of the 6-week periods, all injections were terminated and all rats in linear mazes were transferred to home cages. On test days at intervals of one or more weeks thereafter, the previously morphine-injected rats exhibited higher “wet dog” shake frequencies in their former “abstinence places” (linear maze or home cage) over periods of 155 and 44 days after termination of injections in the two studies, while conditions of previous housing were not systematically related to “wet dog” shake frequencies in the previously saline-injected normal rats.3.In “free choice” tests (etonitazene, 5 meg/kg, versus water) conducted on the nights of the same test days, the previously morphine-injected rats (both studies) drank more of the etonitazene solution than the previously saline-injected normal rats up to 58 days after termination of injections in one study and 44 days in the other, but “trained” and “untrained” previously morphine-injected rats did not differ significantly from each other in this regard.4.It is concluded that although classical conditioning of morphine-abstinence phenomena (and by inference, “craving” for the drug) is demonstrable, the pre-potent factor in disposing to relapse, at least in the rat under the experimental conditions described, is the long-term persistence of unconditioned disturbances in homeostasis following with-drawal of morphine which can provide a source of reinforcement for operant conditioning of opioid-seeking behavior during “relapse-testing” sessions even without benefit of previous “training”.

Conditioning of successive adaptive responses to the initial effects of drugs

Data in the literature indicate that conditioned responses (CRs) generated by repeated pairing of conditional stimulus (CS) with administration of a neurotropic drug may resemble its unconditional effects or they may be opposite in direction; furthermore, the CRs may change as such pairings are continued. In explanation, it is hypothesized that as in conditioning of physiological reflexes, a CS repeatedly paired with administration of a neurotropic drug eventually comes to activate central“processing” events that are evoked by the“stimulus” properties of the drug,i.e., the effects of the drug at receptor sites inside or outside the pia mater which lie in the afferent arms of“reflex” neural circuits; or, the CS comes to activate central processing events that are evoked by centripetal feedback responses to the effects of the drug at receptor sites in the processing or efferent arms of reflex neural circuits. Depending on the receptor site action of the drug, the conditioned autonomic and/or neuromuscular responses that are observed may be in the same direction as, or opposite in direction to the unconditioned effects of the drug. With continued pairings of CS and drug, the unconditioned processing events evoked by the stimulus properties of the drug, and hence the CRs also, change in consequence of compensatory (sometimes“overshooting”) biochemical alterations proximal to the receptor site of action of the drug, induced by negative or positive neuronal feedback mechanisms. These concepts are utilized in a theory of opiate addiction and relapse.

Persistent potency of a secondary (conditioned) reinforcer following withdrawal of morphine from physically dependent rats

Abstract1.On 9 nights (2000-0800) over a 25-day period, an anise-flavored aqueous solution of etonitazene, 5 mcg/ml, was provided as the sole drinking fluid for one group of physically dependent rats (MFETZ) maintained on morphine, 200 mg/kg i.p. once daily at 0800 (hence acutely abstinent each night) and for one group of saline-injected rats (SFETZ), while only anise-flavored water was available to comparable physically dependent (MFH2O) and saline-injected (SFH2O) groups.2.Beginning 3 days after abrupt and permanent termination of morphine or saline injections, all rats were tested at intervals over a period of 287 days on nocturnal (2000-0800) choice drinking from 2 tubes (positions alternated), one contained anise-flavored water and the other, plain water.3.Analyses of variance on the mean volumes of each of the two fluids consumed by each rat over blocks of choice-drinking tests revealed that through the VIIth test (137th post-injection day), MFETZ drank more anise-flavored water than any other group while there were no significant differences among the groups as regards consumption of plain water.4.The evidence indicates that the potency of secondary reinforcers so generated can persist long after morphine withdrawal. Some implications for problems of relapse and treatment of opioid addicts are discussed.

Persistence of "Relapse-Tendencies" of Rats Previously Made Physically Dependent on Morphine *

Summary1.Measurements of 24 hr tap water consumption, body weight, “wet dog” shake frequency and free choice drinking (etonitazene, 5 mcg/ml versus distilled water) were made at intervals up to 434 days following abrupt withdrawal of morphine (from a daily maintenance dose level of 200 mg/kg i.p.) in one group of rats (“postaddicts”) and following termination of i.p. injections of saline in a control group of rats (“normals”).2.During the first five days after termination of injections, signs of primary morphine abstinence were observed in the “postaddict” rats: transient decrease in 24 hr tap water consumption and in body weight, and increase in “wet dog” shake frequency.3.Secondary morphine-abstinence phenomena, consisting of signicantly greater 24 hr tap water consumption and slightly higher “wet dog” shake frequency (compared with normal rats) were observed in “postaddict” rats over the 7th–23rd post-injection days. Thereafter, these differences persisted, but not at significant levels.4.In a no-choice test (etonitazene, 5 mcg/ml or water on different occasions) conducted between the 28th and 37th days after termination of injections, “post-addict” rats drank significantly more etonitazene than water, whereas normal rats drank slightly less etonitazene than water.5.In free-choice drinking tests (etonitazene, 5 mcg/ml versus water) conducted at intervals over a period of 434 days following termination of injections (morphine or saline), no significant differences in mean water consumption between “post-addict” and normal rats were observed. In contrast, “postaddict” rats drank significantly larger mean volumes of the etonitazene solution on every “relapse” test through the 336th and again on the 406th post-withdrawal day (but not on the 372nd or 434th day).6.It is concluded that in the “postaddict” rat a “need” for an opioid persists for about one year after abrupt withdrawal of morphine, and that this “need” is based on long-term derangement of homeostasis. although the physiological characteristics of such homeostatic derangement differ in the relatively short primary and more protracted secondary abstinence periods.7.The long persistence of “relapse-tendency” in rats previously made physically dependent on morphine may be based on such long-term derangement of homeostasis coupled, perhaps, with “interoceptive” conditioning generated during daily cycles of primary abstinence from and relief by morphine in the “addiction” period, through which the internal sensorial effects of opioids (morphine while receiving injections; etonitazene imbibed in “relapse” tests) may acquire secondary reinforcing properties.

Effect of 9 -THC on the open-field activity of the rat.

Using the open-field activity of the hooded rat as a model of overall activity, the dose-response and time-action effects of doses of Δ9-THC which did not adversely affect spontaneous activity or behavior on appetitively motivated tasks were studied. Subjects received two exposures to an open field one week apart. Prior to the first exposure subjects were treated with small doses of Tween 80-water. At 30 min or 3 h prior to the second exposure subjects were treated with Tween or Δ9-THC in doses which ranged from 0.5–5 mg/kg. Results indicated that Δ9-THC affected various indices of open-field activity such as grooming, sniffing and ambulation differently depending on the time after injection. Rearing and defecation were affected similarly by THC independent of post-injection intervals.

The Effect of Intrahypothalamic Microinjection of Hemicholinium (HC-3) on the Hippocampal Theta Rhythm of Cats*

Acute and chronic intact cat preparations were made with recording electrodes located in the dorsal hippocampus and cerebral cortex, stimulating electrodes in the mesencephalic reticular formation, and an “Injectrode” in the posterior hypothalamus through which both electrical and pharmacological stimulation could be applied. In all preparations 12–200 μg hemicholinium (HC-3), administered through the “Injectrode”, suppressed the hippocampal theta rhythm previously elicited by electrical stimulations of either the reticular formation or the posterior hypothalamus. The latency for this effect ranged from 90 min to 3 hours. Reticular-induced desynchronization of the cortical EEG disappeared 2–5 hours after HC-3 administration. Reversal of the HC-3 effect on the hippocampal theta rhythm was seen shortly after administration of carbachol, bethanechol and pilocarpine. No consistent behavioral effects accompanied these changes in EEG. These findings are discussed in light of the hypothesis that HC-3 exerts a post-synaptic action in the CNS, although a pre-synaptic effect through diffusion of the injected HC-3 to a distant site cannot be ruled out with certainty.

Present status of the concept of drug dependence.

At least for heuristic purposes, certain operationally definable concepts of conditioning theory can serve as a framework for research on ‘drug dependence’ both in man and in animals: primary and secondary pharmacological reinforcement, either of which may be direct (‘psychic’) or indirect (‘physical’); and social reinforcement (‘cultural’).

Limbic system and opioid addiction in the rat.

Abstract Statistical comparisons of means in groups of morphine-dependent (or post-dependent) rats with and without bilteral lesions in the cingulum, the dorsomedial thalamic nucleus, the anterior temporal lobe (amygdaloid complex and ventral hippocampus), or the septum, and in nondependent rats with and without such lesions, revealed no significant lesion effects on specific signs of the 24-hr primary morphine-abstinence syndrome in this species: decreased water intake; increased “no-choice” drinking of a 5-μg/ml aqueous solution of a potent opioid (etonitazene); increased “wet dog” shake frequency; fall in colonic temperature. Lesions in the cingulum attenuated one sign of the secondary (protracted) morphine-abstinence syndrome (increased 24-hr water consumption). None of the lesions altered the suppressive effects on the primary morphine-abstinence syndrome of “no-choice” etonitazene-drinking or of intraperitoneal injection of morphine. None of the lesions prevented “relapse” of postdependent rats, as measured by comparisons of mean volumes of etonitazene (5-μg/ml) and water consumed in “choice” trials 9–72 days after permanent withdrawal of morphine.

Marijuana: effects on storage and retrieval of prose material.

In a two phase design, an attempt was made to differentiate the effect of marijuana on the storage and retrieval of prose material. In the first phase, 40 male subjects were administered a single 500 mg marijuana cigarette containing 2.1% Δ9-TCH or a placebo cigarette. Fifteen minutes after smoking, they listened to and at the same time read a narrative passage of approximately 200 words in length. Subsequently, an immediate free recall test was given in which subjects were required to write down as much of the story as they could remember. The second phase was conducted 24 h later. Marijuana and placebo subjects were randomly subdivided into four groups with half of the subjects participating in the same drug condition as occurred on day one while the others switched drug state. Fifteen minutes after smoking, all subjects recalled the passage pressented on day one and then were given 24 questions concerning facts and events in the story which could be answered in a few words. These questions served as retrieval cues. Following this, a new passage was presented in the same manner as occurred on day one. After an immediate free recall test, another cued recall test was administered.Results indicated that marijuana reduced immediate recall under both cued and uncued conditions in comparison to placebo. No relative cued recall advantage was found in the marijuana groups for the old or new story and marijuana produced only a moderate decrement in recall of the old story on day two. However, marijuana given in the second phase significantly reduced memory for items recalled in the initial phase irrespective of drug or cueing condition in phase one, suggesting that retrieval was also affected. Some decrement in recall of the new story did occur as a function of drug state change in group M-P. This effect was related to the serial position of input items. Serial position did not interact with drug state under any other recall condition.

Marijuana and memory impairment: the effect of retrieval cues on free recall☆

In an attempt to ascertain the effect of retrieval cues on recall deficits which occur following intoxication with marijuana, 40 male volunteers were presented with word lists following the smoking of a single one gram marijuana (0.94% delta 9 -THC) or placebo cigarette and then were required to recall these words immediately after presentation. Recall occurred under a condition in which cues representative of to-be-remembered words were present or in an uncued condition. Results indicated that recall was depressed following marijuana administration under both cued and uncued conditions with cues being only mildly effective in reversing the recall deficit. There was no increase in the number of internal intrusions under marijuana, but the number of external intrusions was significantly elevated under the cued conditions.