Frank A. Holloway

Multiphasic Retention Deficits at Periodic Intervals after Passive-Avoidance Learning

Aftetr one-trial passive-avoidance training, indepelenet groups of rats tested promptly after training or at successive 6-hour intervals displayed a repetitive pattern of high then low retention scores. These results suggest that some physiological rhythm may interact with retention performance.

Multiple retention deficits at periodic intervals after active and passive avoidance learning.

In separate experiments with independent groups of rats, retention performance after either a one-trial, passive avoidance or a multi-trial, one-way active avoidance training session was examined as a function of one of six training-testing intervals (15 min, 6 hr, 12 hr, 18 hr, 24 hr, or 30 hr) and of one of our training times (0300, 0900, 1500, or 2100 hr). All animals were entrained on a 12-hr light, 12-hr dark schedule. Retention performance for both active and passive avoidance tasks was best when testing was done at approximately the same time as training (i.e., 15 min or 24 hr later), regardless of the time of training. Retention performance for both tasks was poorest in groups tested 6, 18 or 30 hr after training, again regardless of the time of training. Retention performance in the groups tested 12 hr after training was intermediate to the 15-min or 24-hr groups and the 6-, 18- or 30-hr groups, the degree of impairment depending somewhat on time of training. Such data suggest that some recurring process like a biological rhythm may mediate the fluctuations in retention performance. The authors discuss a state-dependent hypothesis in which the state of the organism at the time of training becomes associated with the conditioning experience and shifts towards or away from that state influence retention performance via the availability of relevant cues.

Cocaine and Caffeine: Conditioned Place Preference, Locomotor Activity, and Additivity

Conditioned place preference (CPP) was employed to clarify the reinforcing and locomotor stimulating effects of several doses of cocaine and caffeine (0.32, 1.0, 3.2, 5.6, and 10.0 mg/kg) and to explore the possibility of additive effects between the two drugs. Additionally, the hypothesis that the reinforcing effects of psychostimulants are mediated by the same systems that control psychostimulant-induced locomotor activity was examined by conducting correlational studies between drug-induced locomotor activity and time spent in the drug-conditioned compartments. Several doses of cocaine (1.0, 3.0, 5.6, 10.0 mg/kg), and caffeine (0.32, 1.0, 3.2, 5.6, 10.0) were found to condition place preference and stimulate locomotor activity. A combination of low doses (0.32 mg/kg) of each drug appeared to be additive. A positive relationship between locomotor activity observed during conditioning and time spent in the conditioned compartment during testing was found for cocaine but not caffeine or the low-dose combination of cocaine and caffeine.

State-dependent effects of ethanol on active and passive avoidance learning

The present set of experiments examined the importance of the response initiation-inhibition parameter of certain avoidance conditioning tasks in the production of state-dependent dissociative effects with ethanol. On those tasks involving some degree of response inhibition (passive avoidance and two-way active avoidance), animals receiving ethanol during training were more impaired in their testing performance than those receiving saline during training (anterograde amnestic effect), and animals injected with ethanol during training and saline during testing displayed dissociation of their acquired avoidance behaviors during testing (asymmetrical dissociation effect). On the task involving a response initiation element with little contamination by response suppression factors (one-way active avoidance), dissociation of avoidance behavior during testing was found both for the animals trained under ethanol and tested under saline and for the animals trained under saline and tested under ethanol (symmetrical dissociation effect). The results were discussed in terms of possible joint effects of symmetrical state-dependency and other behavioral properties of the drug. However, an alternative interpretation could not be ruled out, namely that the mechanisms involved in the impairment found on the testing day for the drug-placebo and placebo-drug groups may be different. It was suggested that the drug-placebo group may represent the more general example of state-dependent dissociation effects, whereas the production of state-dependent dissociation effects in the placebo-drug group may depend upon the type of behavior conditioned and/or the strength of such conditioning.

Cold water stress analgesia in rats: differential effects of naltrexone.

Cold water swim (CWS, 2 degrees C, 3.5 min) decreases the responsiveness to nociceptive stimuli in rats. The influence of various parameters of the CWS condition on stress-induced analgesia were evaluated by means of naltrexone effects. Naltrexone dose-dependently (but significantly only at high doses--21 mg/kg) partially antagonized 3.5 minute continuous CWS analgesia. Its effect was proportional to the duration of CWS. Naltrexone (14 mg/kg) significantly antagonized intermittent CWS-analgesia (18 10-sec exposures, 3/min) and enhanced the analgesia induced by 60 consecutive exposures (1 sec each, 12/min). These results demonstrate that naltrexone differentially affects CWS-analgesia, depending on specific parametric conditions of the stressor. In addition to activation of a non-specific naltrexone-insensitive analgesia-inducing system (not reduced by the drug in all the conditions studied) there appear to be three naltrexone sensitive systems: (1) a non-opioid analgesia-inducing system which mediates continuous CWS-analgesia; (2) an opioid analgesia-inducing system, involved in intermittent CWS-analgesia; and (3) a naltrexone-sensitive system which opposes the analgesic effect of 60 consecutive exposures. Thus, a highly specific relationship exists between certain parameters of the cold water stressor and the nature of the mechanisms which subserve the induced analgesia.

Multiple retention deficits following one-trial appetitive training.

Retention performance in independent groups of rats was examined at various intervals following one-trial appetitive maze training in which water reinforcement was available in the goal box. A control procedure minimized deprivation differences between the various groups. Results of this first experiment indicated multiple retention deficits similar to those previously found only for avoidance behaviors. Retention was significantly better in the 12 hr, 24 hr, and 36 hr groups than in the 6 hr, 18 hr, and 30 hr groups. Performance by the 0.25 hr and 1 hr groups was intermediate. A second experiment was designed to determine whether non-reinforced behavior in the same apparatus would also fluctuate periodically. The performance of rats in this experiment did not parallel the rhythmic pattern of the rats in Expt I. These periodic performance fluctuations in Expt I are explained in terms of “state-dependent” retrieval based upon some internal biological rhythmic process, in which footshock induced factors apparently play a minimal role.

Potentiation of cocaine's discriminative effects by caffeine: A time-effect analysis

The effects of caffeine upon the discriminative and rate-altering effects of cocaine were examined in rats. Using a food-reinforced two-lever operant procedure, 12 male Sprague-Dawley rats were trained to discriminate between 10 mg/kg cocaine and saline. Time-effect analysis of the training dose resulted in a median effective time interval (the duration of the discriminable effects of cocaine in producing 50% cocaine-appropriate responding), of 60.5 minutes postinjection. Caffeine partially generalized to the cocaine stimulus and, when administered with cocaine, produced a dose- and time-dependent increase in the percentage of drug-appropriate responding. Data are discussed with reference to our previous results with cocaine-caffeine interactions.

Conditioned place aversion to the “hangover” phase of acute ethanol administration in the rat

The purpose of this study was to examine ethanols delayed effects (termed hangover) using conditioned place testing. Four groups of rats received a single pairing of a distinctive environment (tactile and visual) 10 h after injection with ethanol (0, 2, 3, 4 g/kg, i.p. ) or saline in a counterbalanced design. Rats receiving 3 and 4 g/kg ethanol showed a conditioned place aversion to ethanol hangover. Conditioning 10 h after 0 or 2 g/kg ethanol did not produce a significant place preference or aversion. The results suggest that the hangover following an acute injection of high doses of ethanol (3-4 g/kg) produces a significant and dose-related conditioned place aversion in the rat.

Aversive attributes of ethanol can be attenuated by dyadic social interaction in the rat

Forty-eight male Sprague-Dawley rats were conditioned with either water or 4 g/kg ethanol in a standard drug place-learning task. In addition to the drug treatment, the opportunity for social interaction with either a sober or intoxicated conspecific was varied across groups (N = 8 rats/group). Ethanol produced a robust conditioned place aversion. The opportunity for dyadic social interaction with either a sober or intoxicated cohort attenuated the aversive attributes of ethanol. However, the initial preference scores did not significantly shift in water-conditioned rats in isolation or given access to either a sober or intoxicated cohort. These data are similar to clinical reports and suggest that social factors can influence the aversive affective properties of ethanol.

Role of context in ethanol tolerance and subsequent hedonic effects

Two groups of male Sprague-Dawley rats received ethanol dose-effect tests for FR30, food-reinforced operant performance, in each of two environmental contexts, before and after a period of daily presession ethanol or saline injections. During the latter period, context alternated daily. The ethanol group received ethanol prior to sessions for one context and saline, prior to sessions for the other context. The saline group always received presession saline. The ethanol, but not the saline, group displayed robust tolerance to ethanols rate-decreasing effects, with no difference between tests in each context. Both groups then received training and testing in an ethanol-conditioned place preference task. The saline group displayed significant avoidance of the compartment paired with ethanol. The ethanol group displayed no initial aversion for the ethanol compartment and, with extended conditioning, showed a significant increase in time spent in the ethanol compartment. We suggest that this tolerance represents context-independent, learning to compensate for ethanol-induced effects, and that this tolerance subsequently blocked the conditioned place aversion evident in nontolerant controls, thereby enhancing the estimates of ethanols reward properties.