Differential Reinforcement Of Low Rates Research Articles

DRL performance in mice with deletion of tPA, uPA or PAI-1 genes.

Plasminogen activators are serine proteases induced in the brain by electrical activity leading to synaptic remodelling. They are classified into two distinct subtypes, tissue plasminogen activating factor and urokinase plasminogen activating factor (tPA and uPA, respectively), which are both expressed in brain areas thought to be important in learning and memory. Plasminogen activator inhibitor-1 (PAI-1) is the primary inhibitor of tPA and uPA activity, and is expressed in corresponding brain areas. Mice lacking tPA show a deficit in the acquisition of a 15 s differential reinforcement of low rate of responding (DRL15") task relative to their wild types (WTs) under certain conditions. The current set of experiments were designed to investigate further the role of tPA and to extend our knowledge to uPA and PAI-1, using mice with the respective genes deleted (uPA -/- and PAI-1 -/- mice) in the DRL15" task. uPA -/- mice showed no disruption of DRL acquisition, but PAI-1 -/- mice showed a deficit similar to that seen in tPA -/- mice. In an attempt to compensate for this deficit, experiments using a fixed number of reinforcers or a signalled-DRL15" schedule, similar to that used in rat lesion studies of DRL, were performed. tPA -/- mice were able to complete the signalled-DRL task as well as their WTs, and, similarly, PAI-1 -/- mice were able to learn the fixed-number-of-reinforcers-DRL15" schedule and the signalled-DRL schedule. These data indicate that uPA deletion does not affect performance of a standard DRL15" task, whereas deletion of PAI-1 has the same behavioural consequences in these tasks as deletion of tPA. Deficits of both genotypes can be attenuated by providing either external information on completion of the delay or by equalizing the number of reinforcers obtained.

Evidence for impairment of behavioural inhibition in performance of operant tasks in tPA−/− mice

We have previously shown that mice that lack the serine protease, tissue plasminogen activator (tPA), show over-responding on the active lever during time-out periods in an I.V. cocaine self-administration task. To investigate this effect further, tPA knockout mice (tPA−/−) were tested in a number of operant paradigms for a liquid food reinforcer. tPA−/− and wild-type (WT) control mice acquired a fixed ratio (FR) and a fixed interval (FI) task equally. However, extinction from the FR schedule resulted in a significant decrease in responses on the active and inactive levers in the WT mice whilst responding on the inactive lever remained high in the tPA−/− animals. In a differential reinforcement of low rate (DRL) task, tPA−/− mice acquired the task at a slower rate than WT animals. This was characterised by high levels of responding on the active lever during the first 15 sessions in the tPA−/− mice. Burst responding on the active lever (lever press rate with an inter-response time of less than 3 s) was especially high in these animals. This behaviour pattern resulted in the animals obtaining less reinforcers than the WT controls. Acute cocaine dose-dependently shifted the pattern of behaviour on the active lever towards shorter inter-response times. However, there was no difference between the tPA−/− and WT mice in their sensitivity to cocaine on this task. Repeated administration of a low dose of cocaine did not alter performance on this task in either set of animals. When the DRL task was modified to allow the tPA−/− and WT mice an equal number of reinforced trials per session there was no difference in the ability of the animals to perform the task. This would suggest that the tPA−/− mice have a tendency to over-respond but that this can be overcome when the task is modified to allow equal opportunity to learn.

Spontaneous activity as a contingency-controlled behavior within an operant context: alprazolam concentration-effect relations after subcutaneous administration in rats.

Environmental factors affect serum drug concentration-effect relations. For example, after midazolam administration, longer pre-session delays imposed in experimental chambers produced differential concentration-effect relations compared to those of shorter delays. To evaluate the extent to which serum concentrations determine alprazolam's effects on spontaneous activity in the presence and absence of a differential reinforcement of low rate (DRL 45-s) contingency using pharmacokinetic-pharmacodynamic analysis. Serum concentrations reported here were simulated from our published pharmacokinetic parameters for alprazolam. One group (n=8) was used to investigate alprazolam's effects on spontaneous activity within the DRL contingency by placing an activity platform beneath each operant chamber to monitor concurrently both spontaneous activity (large and small movements) and DRL performance (shorter-response and reinforcement rates) in 3-h sessions; a parallel group (n=7) was used without the operant context. The concentration-effect relation of the reinforcement rate was compared and contrasted with those of spontaneous activity. Alprazolam decreased large and small movements within the DRL contingency, which corresponded to that of reinforcement rates under the DRL 45-s schedule. In contrast, without the DRL contingency, alprazolam's effects on small movements were short-lived (i.e., 30 min) and no effects on large movements were detected. Hence, the predicted concentration-effect relations for the reinforcement rate function described those of spontaneous activity well within the operant context, but not those without the operant context. Furthermore, the latter showed no correlation between serum alprazolam concentration and large movements; a significant, but low negative correlation for small movements was observed. The duration of alprazolam's action was dependent on not only dose size but also the behavioral measure examined. By imposing the DRL contingency, spontaneous activity behaves as an ideal pharmacodynamic measure (i.e., continuous, sensitive, and objective).

Combinations of clozapine and phencyclidine: effects on drug discrimination and behavioral inhibition in rats

Phencyclidine (PCP) produces psychotomimetic effects in humans that resemble schizophrenia symptoms. In an effort to screen compounds for antipsychotic activity, preclinical researchers have investigated whether these compounds block PCP-induced behaviors in animals. In the present study, the atypical antipsychotic clozapine was tested in combination with an active dose of PCP in two-lever drug discrimination and mixed signalled–unsignalled differential-reinforcement-of-low-rates (DRL) procedures. PCP produced distinctive effects in each task: it substituted for the training dose in PCP discrimination and it increased the number of responses with short (<3 s) interresponse times as well as increasing overall response rates in the DRL schedule. Acute dosing with clozapine failed to alter the behavioral effects of PCP in either procedure even when tested up to doses that produced pharmacological effects alone. These results suggest that acute dosing with clozapine would not affect behaviors most closely associated with PCP intoxication. Further, they bring into question the utility of using PCP combination procedures in animals to screen for antipsychotic potential. Since chronic dosing is required for therapeutic efficacy of antipsychotics, future studies should focus on investigation of chronic dosing effects of these drugs in combination with PCP.

Contribution of the active metabolite, norcocaine, to cocaine's effects after intravenous and oral administration in rats: pharmacodynamics.

Oral cocaine is more effective than IV cocaine by pharmacokinetic and pharmacodynamic analysis. One explanation is involvement of the active metabolite, norcocaine, in cocaine's effects. To evaluate norcocaine's contribution to oral cocaine's effects, norcocaine's effects as a parent compound were determined and compared to those of cocaine using a differential reinforcement of low rate (DRL 45-s) schedule and spontaneous activity (large and small movements) after IV and PO routes of administration. The effects of cocaine and norcocaine on DRL performance (shorter-response and reinforcement rates) and spontaneous activity were investigated in 3-h sessions. The changes in effects across time (effect-time profiles) and dose-response curves (DRCs) were constructed to evaluate the duration of action and potency (ED50) of both drugs. Under the DRL 45-s schedule, effect-time profiles showed both drugs via the two routes of administration significantly increasing and decreasing shorter-response rates and reinforcement rates, respectively. However, cocaine produced greater effects on shorterresponse rates than norcocaine, while both drugs produced comparable effects on reinforcement rates. For spontaneous activity, although IV cocaine, PO cocaine, and PO norcocaine dose- and time-dependently increased spontaneous activity, cocaine's effects were more profound than those of norcocaine. Effect-time profiles revealed that the duration of drug action was a function of dose, route, and behavioral paradigm used. According to ED50 values, IV cocaine was more effective than PO cocaine; however, PO cocaine was more effective than IV cocaine as judged by ED50 values corrected for absolute oral bioavailability. Norcocaine's contribution to oral cocaine's effects on DRL performance is evident. Other mechanism(s), such as a greater acute tolerance to IV cocaine's effects than to PO cocaine's effects, can be excluded.

Comparison of drug effects on the performance of two timing tasks in rats

Previous evidence suggests that different timing tasks are differentially sensitive to pharmacological manipulation, especially when different values for the temporal parameters are used. The present series of experiments compared the effects of physostigmine, caffeine, pentobarbital, morphine, and naloxone on the performance of a differential reinforcement of low rates with limited hold (DRL-LH) and a temporal response differentiation (TRD) task. In the DRL-LH task, rats were reinforced for responses that occurred 10–14 s from the end of the previous response. In the TRD task, rats were reinforced for responses with a duration of 10–14 s. The peak response time and peak spread of the initiation time distribution (for DRL-LH) or the response duration distribution (for TRD) were used as indices of temporal discrimination. Physostigmine, caffeine, and pentobarbital produced very similar effects on peak response time for both tasks, but the effects of morphine and naloxone were different for the two tasks. Effects on peak spread for the two tasks did not always correspond to changes in peak response time, suggesting that different processes may be measured by these two endpoints. Further, these effects were independent of changes in response rate suggesting that the effects were not due to gross disruptions in motivation or motor control. These results suggest that the effects of drugs on DRL-LH and TRD performance may differ, even when temporal parameters are identical.

Common Firing Patterns of Hippocampal Cells in a Differential Reinforcement of Low Rates of Response Schedule

Lesion studies show that the hippocampus is critically involved in timing behavior, but so far there has been little analysis of how it might encode time. We recorded the activity of 266 CA1 neurons, 51 CA3 neurons, and 219 entorhinal neurons from rats performing on a differential reinforcement of low rates (DRL) 15 sec schedule in which reinforcement was contingent on responses that occurred at least 15 sec after the preceding response. The unit data were analyzed using two different methods. First, each unit was subjected to an ANOVA that examined the effects of the following: (1) the outcome of the previous response (reward or nonreward); (2) the outcome of the response on which the firing of the cell was synchronized; and (3) time. This showed that, for CA1, CA3, and entorhinal cortex, changes in unit activity were related to all aspects of the task, with the firing of >90% of units recorded in each region being related to at least one of the three factors. Second, intercorrelations between the firing profiles of individual units revealed several functional categories of hippocampal neurons but no clear categories of entorhinal neurons. Of the hippocampal categories, the most common profile was an initial increase in unit activity at the beginning of the DRL interval, followed by a gradual decrease throughout the interval. We suggest that this profile reflects temporal decay in circuits that may code details of the previous trial and that could be used to "time" the DRL interval.

The differential reinforcement of low-rate (DRL) 72 model for characterization of antidepressant agents: Noradrenaline, but not serotonin or dopamine, uptake inhibitors mimic the actions of imipramine

The differential reinforcement of low-rate (DRL) 72 model for characterization of antidepressant agents: Noradrenaline, but not serotonin or dopamine, uptake inhibitors mimic the actions of imipramine

Effects of nitric oxide synthase inhibitors on timing and short-term memory in rats.

Nitric oxide synthase (NOS) inhibitors have been shown to affect the development of long-term potentiation and the acquisition of new learning. In the present study, we investigated the effects of NOS inhibitors in two animal models in which aspects of cognition are measured in well-learned operant tasks - a delayed non-match-to-position (DNMTP) task and a multiple signalled-unsignalled differential reinforcement of low rates (DRL) 15 s schedule - models of short-term memory and behavioral inhibition/timing, respectively. Since an overlap in the behavioral effects of NOS inhibitors and phencyclidine (PCP)-like N-methyl-D-aspartate (NMDA) antagonists has been observed previously, we compared our results with NOS inhibitors to those obtained with PCP. Whereas PCP produced a delay-independent decrease in the DNMTP task and increased burst responding (consecutive responses with inter-response intervals of < 3 s) in both the signalled and unsignalled components of the DRL procedure, 7-nitroindazole did not affect accuracy in the DNMTP task nor did it alter the pattern of responding in either component of the DRL schedule. Similarly, NG-nitro-L-arginine (L-NOARG) and NG-nitro-L-arginine-methyl-ester (L-NAME) did not affect accuracy in the DNMTP task. These results suggest that NOS inhibitors do not produce PCP-like disruption of behavioral inhibition or timing, nor do they decrease accuracy in a conditional discrimination task, as has been observed with PCP. The present results lend further support to the hypothesis that nitric oxide modulation does not affect retention of well-learned tasks, although it may affect acquisition of novel behavior.

Separation of drug effects on timing and behavioral inhibition by increased stimulus control.

Impulsive behavior may represent, in part, a failure of behavioral inhibition (the ability to delay or inhibit a response). In this study, use of a multiple signaled-unsignaled differential-reinforcement-of-low-rates (DRL) 15-s schedule allowed examination of drug effects in conditions in which level of stimulus control differed. Results showed that whereas diazepam increased premature responding during signaled and unsignaled DRL components, amphetamine and delta9-tetrahydrocannabinol increased premature responding primarily during unsignaled components when timing was necessary for efficient performance on the task. In contrast, pimozide and desipramine increased long-delay responses across both components, resulting in longer mean interresponse times. Collectively, these results suggest that the use of different levels of stimulus control may aid in separation of drug effects on timing and other behavioral processes, including behavioral inhibition.

Dose-dependent effects but not sensitization of DRL 45-s performance by oral d-amphetamine with cumulative- and repeated-dosing regimens.

The effects of d-amphetamine (AMPH) on a food-reinforced DRL 45-s schedule were evaluated using both cumulative- and repeated-dosing drug regimens. These two dosing regimens were designed to evaluate sensitization as a shift in the dose-response relationship, inasmuch as a range of doses was imposed within each dosing session. Daily 190-min sessions were composed of five 35-min subsessions separated by 3-min time-out periods. For selected sessions, five cumulative or repeated oral doses of AMPH were administered across the session, with a dose given during each of the time-out periods prior to the start of each subsession. Drug sessions were separated by intervals of 7-l0 days of non-drug sessions. Four cumulative dose-effect functions for AMPH were determined: for each dose-effect determination session, increasing doses (0.5, 1, 2, 4, 8 mg/kg gavage) were successively administered prior to each subsession. Four dose-effect functions were then determined in which a 0.5 mg/kg AMPH dose was repeated for each subsession (repetitive-dose regimen) rather than escalating subsession dose size. Then, four additional functions were determined using a larger repetitive dose of 1 mg/kg AMPH. Cumulative doses resulted in a leftward shift in the inter-response times (IRT) distribution accompanied by dose-dependent increases in subcriterion responses (< 45 s) and decreases in reinforced responses. The repeated doses of 0.5 or 1 mg/kg AMPH also resulted in progressive intrasession increases in subcriterion responses and decreases in reinforced responses. Although intrasession, accumulating dose effects were evident and statistically significant, there was no statistical significance or trend supporting sensitization of differential reinforcement of low-rate (DRL) responding with either cumulative- or repeated-dosing regimens across drugging sessions, unlike a previous, similar study in which oral cocaine resulted in robust sensitization.

Mimosa pudica may possess antidepressant actions in the rat.

In Mexico, aqueous extracts from dried leaves of Mimosa puolica are employed to alleviate depression. In this study, the behavioral actions of aqueous extracts of M. pudica at various concentrations were tested. Rats having received saline (0.9%; 0.30 ml; I.P.), clomipramine, desipramine or several dosages of aqueous extracts from M. pudica (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) during a 30-day period were submitted to the forced swimming test and to the test for differential reinforcement of low rates of response at 72 sec (DRL-72s). Any possible anxiolytic action resulting from several doses (ml = 2.0 mg/kg; m2 = 4.0 mg/kg; m3 = 6.0 mg/kg; m4 = 8.0 mg/kg) of extracts of M. pudica were compared with those caused by diazepam (1.3 mg/kg, I.P.) in the elevated plus-maze test. Results showed that clomipramine (1.25 mg/kg, I.P.), desipramine (2.14 mg/kg, I.P.) and M. pudica (6.0 mg/kg and 8.0 mg/kg, I.P.) reduced immobility in the forced swimming test and increased the rate of reinforcers received in the DRL-72s test; these data suggest that M. pudica produces antidepressant effects in the rat. Diazepam increased the open-arms exploration time in the elevated plus-maze test, but M. pudica did not show any comparable action at any tested dose. M. pudica therefore produced an antide-pressant-like profile similar to two tricyclic antidepressants.

The use of timing behaviors in animals and humans to detect drug and/or toxicant effects.

Behavioral paradigms applicable for use in both human and nonhuman subjects for investigating aspects of timing behavior are presented with a view towards exploring their strengths, weaknesses, and utility in a variety of experimental situations. Tri-peak, peak interval, differential reinforcement of low rate responding, and temporal response differentiation procedures are highlighted. In addition, the application of timing tasks in preclinical and clinical settings is discussed: pharmacological manipulations are providing information on the neurotransmitters involved and species differences; normative data for children are being developed; and noninvasive imaging procedures are being employed in adult human subjects to explore the involvement of specific brain areas.

Behavioural effects in female rats of postnatal exposure to sub-toxic doses of polychlorinated biphenyl congener 153

Polychlorinated biphenyls (PCBs) are widespread environmental contaminants that are also present in human tissues and breast milk. Behavioural disturbances have been reported in both children and animals exposed perinatally to PCBs. The present study assessed the behavioural consequences in female rats of postnatal exposure to the di-ortho-substituted 2,2′,4,4′,5,5′-hexachlorobiphenyl (IUPAC no. 153), which is one of the PCB congeners most frequently detected in human milk. The different groups of mothers were dosed via gavage with 5 mg/kg bodyweight of PCB 153 in corn oil or 5 ml/kg bodyweight corn oil vehicle every second day from day 3 to day 13 after delivery. The exposure did not affect the bodyweight of the dams nor the physical development of the pups. Operant behavioural testing of the female offspring by two different schedules of reinforcement was performed. First, the animals were tested by a multiple schedule with two components: fixed interval (FI) and extinction (EXT), which has proved sensitive in revealing changes in activity level. There were no statistically significant differences in frequency or interresponse times of lever pressing between the PCB-exposed female rats and the controls. These results were in contrast to a previous, analogous study where PCB 153 produced an increased frequency of lever presses during the FI in male rats, indicating a sex-specific behavioural effect of PCB 153. The female offspring was also tested by a conjunctive schedule with two components: variable interval (VI) and differential reinforcement of low rate (DRL). This schedule revealed slower acquisition of time discrimination in the PCB 153-exposed females as compared with the controls. The VI-DRL results showed that PCB 153 may also produce long-lasting behavioural effects in female rats following postnatal exposure through the mother's milk.

Effects of the group II metabotropic glutamate receptor agonist, LY354740 on schedule-controlled behaviour in rats.

The present study examined the effect of the novel, systemically active Group II metabotropic glutamate (mGlu) receptor agonist, LY354740, on schedule-controlled behaviour in rats. Responding for food reward was maintained by three different operant procedures; the first, a three-component conflict schedule; the second, a multiple fixed-interval 60 s/fixed-ratio 10 (FI60/FR10) schedule and the third, a differential reinforcement of low rates of responding 10 s (DRL10) schedule. In the first procedure, rats were trained to respond for food on a schedule comprising of variable-interval 30 s (food, VI30) and fixed-ratio 10 (food + shock, FR10) components separated by time-out (TO). LY354740 (1.25-5 mg/kg, i.p.) produced a dose-related reduction in responding during the VI component and increased responding during the TO component, while having no effect on responding during the punished FR10 phase. In the FI60/FR10 schedule, LY354740 produced a dose-related reduction in the high rates of responding observed during the FR10 component of the schedule. Although LY354740 (0.6-10 mg/kg, i.p.) had no effect on the overall response rates produced by the FI60 component, there was a shift in the temporal distribution of responding as measured by the quarter-life. LY354740 (10 mg/kg, i.p.) increased the low rates towards the start of the interval, while decreasing the rates of responding towards the end of the FI60 period. In the DRL10 s schedule, LY354740 (5-20 mg/kg, i.p.) had no effect on the total number of responses but produced a significant reduction in the total number of rewards, suggesting that the temporal control of responding had been disrupted. The changes in operant responding occurred at doses that decreased exploratory behaviour. In summary, LY354740 modified responding maintained by all three operant schedules at doses which suppressed spontaneous activity. These data demonstrate that stimulation of Group II mGlu receptors can produce changes in responding which are dependent on the base-line rate of responding, suggesting that mGlu 2/3 receptors may be involved in the stimulus and temporal control of behaviour.

Behavioral Effects of Family-Selective Inhibitors of Cyclic Nucleotide Phosphodiesterases

O’DONNELL, J. M. AND S. FRITH. Behavioral effects of family-selective inhibitors of cyclic nucleotide phosphodiesterases. PHARMACOL BIOCHEM BEHAV 63(1) 185–192, 1999.—The effects of family selective inhibitors of phosphodiesterase (PDEl, PDE2, PDE3, PDE4, and PDE5) on the behavior of rats under either a differential-reinforcement-of-low-rate (DRL) 72-s schedule or a variable-interval (VI) 30-s schedule were determined; previous work has shown that antidepressant drugs increase reinforcement rate under long DRL schedules. The PDE4-selective inhibitor rolipram (0.03–0.1 mg/kg) reduced response rate and increased reinforcement rate under the DRL schedule in a dose-dependent manner; similar effects were observed with the tricyclic antidepressant drug desipramine (3–10 mg/kg). Both of these drugs produced biphasic effects on behavior maintained under the VI schedule, increasing response rate at the lower doses tested (rolipram: 0.003 mg/kg; desipramine: 0.03 mg/kg) and decreasing response rate at higher doses (rolipram: 0.1 mg/kg; desipramine: 0.3–18 mg/kg). Of the other PDE inhibitors tested, only the PDE5-selective inhibitor zaprinast (10 mg/kg) produced an antidepressant-like effect on DRL behavior. However, in contrast to the biphasic effects of rolipram and desipramine on VI behavior, zaprinast produced monotonic decreases in response rate (10–30 mg/kg). The PDE2-selective inhibitor trequinsin produced biphasic effects on response rate under the VI schedule, increasing rates at low doses (3–5.6 mg/kg) and decreasing rates at higher doses (18–30 mg/kg). Trequinsin also reduced response rate under the DRL schedule (30 mg/kg); however, the reduction in response rate was not accompanied by increased reinforcement rate. The PDE3-selective inhibitor milrinone (1–10 mg/kg) tended to increase response rates under both schedules while the PDE1-selective inhibitor vinpocetine did not affect behavior at the dose range tested (1–30 mg/kg). These findings suggest that inhibition of PDE4 results in a rather unique pattern of behavioral effects, most notably an antidepressant-like effect on DRL behavior. It remains to be determined if a similar effect produced by zaprinast also implicates PDE5 in the mediation of antidepressant activity or represents an effect of this drug on PDE4 activity at high doses.

Sensitization of operant behavior to oral cocaine with increasing- and repetitive-dose regimens.

This study evaluated whether operant behavior was subject to sensitization upon repeated exposure to cocaine. The behavior of eight rats was reinforced by food-pellet delivery under a differential reinforcement of low-rate (DRL) 45-s schedule, in daily sessions of 190 min. Each session was composed of five 35-min subsessions, with each subsession preceded by a 3-min time out period (TO). For selected sessions, a cumulative dose-effect relation for cocaine, using increasing doses, was first determined by oral gavage administration of a dose during each subsession. Three such cycles were given, separated by between seven and ten sessions. Later, four further cycles were given, using a repetitive 10 mg/kg cocaine per os (p.o.) dose, rather than an increasing dose. Under both dosing procedures, within a cocaine cycle (session), shorter (<45 s) inter-response times (IRT) progressively increased with doses, and reinforced responses decreased. As cycles were repeated, the shorter IRT increases became progressively more marked, indicating the development of sensitization to the effect of cocaine. With the second procedure (repetitive 10 mg/kg doses), reinforcement rate decreases became more marked as cycles were repeated, but this change did not occur using the increasing-dose procedure. Upon later exposure to repetitive 5 mg/kg dosing cycles, none of these rate changes occurred, and performances were equivalent to those occurring under saline cycles. Exposure to cumulative dose regimens of oral cocaine can result in the sensitization of operant behavior to the effects of cocaine.

Double dissociation of function within the hippocampus: A comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions.

Rats with complete cytotoxic hippocampal lesions exhibited spatial memory impairments in both the water maze and elevated T maze. They were hyperactive in photocell cages; swam faster in the water maze; and were less efficient on a nonspatial, differential reinforcement of low rates (DRL) task. Performance on both spatial tasks was also impaired by selective dorsal but not ventral lesions; swim speed was increased by ventral but not dorsal lesions. Both partial lesions caused a comparable reduction in DRL efficiency, although these effects were smaller than those of complete lesions. Neither partial lesion induced hyperactivity when rats were tested in photocell cages, although both complete and ventral lesion groups showed increased activity after footshock in other studies (Richmond et al., 1999). These results demonstrate possible functional dissociations along the septotemporal axis of the hippocampus.

Double dissociation of function within the hippocampus: a comparison of dorsal, ventral, and complete hippocampal cytotoxic lesions.

Rats with complete cytotoxic hippocampal lesions exhibited spatial memory impairments in both the water maze and elevated T maze. They were hyperactive in photocell cages; swam faster in the water maze; and were less efficient on a nonspatial, differential reinforcement of low rates (DRL) task. Performance on both spatial tasks was also impaired by selective dorsal but not ventral lesions; swim speed was increased by ventral but not dorsal lesions. Both partial lesions caused a comparable reduction in DRL efficiency, although these effects were smaller than those of complete lesions. Neither partial lesion induced hyperactivity when rats were tested in photocell cages, although both complete and ventral lesion groups showed increased activity after footshock in other studies (Richmond et al., 1999). These results demonstrate possible functional dissociations along the septotemporal axis of the hippocampus.

Effects of postnatal exposure of monkeys to a PCB mixture on spatial discrimination reversal and DRL performance.

Behavioral impairment as a consequence of PCB exposure beginning in utero has been reported in both humans and animals. The present study assessed the behavioral consequences of postnatal exposure to PCBs. Male monkeys (Macaca fascicularis) were dosed from birth to 20 weeks of age with 7.5 microg/kg/ day of a PCB mixture representative of the PCBs typically found in human breast milk (eight monkeys) or vehicle (four monkeys). Blood PCB levels at 20 weeks of age were 0.30-0.37 ppb for control and 1.84-2.84 ppb for treated monkeys, and fat levels were 50-198 and 1694-3560 ppb for the two groups, respectively. At about 4.5-5.0 years of age, monkeys performed on a series of three spatial discrimination reversal tasks, followed by a differential reinforcement of low rate (DRL) 30-s schedule of reinforcement. There were no differences between groups for the number of errors across reversals for any of the discrimination reversal tasks, whereas the PCB-treated group tended to have shorter median response latencies than the control group. On the DRL schedule, there were robust differences in performance between the treated and control groups. Treated monkeys displayed shorter mean and median interresponse times (IRTs), obtained fewer reinforcements, and emitted more nonreinforced responses. The treated groups also had more short IRTs (< or =10 s) than control monkeys. Performance of the treated group did not improve to control levels over the 51 sessions of the DRL 30-s schedule; their performance remained much less efficient than that of controls. The results of this study extend previous research in this cohort of monkeys, and provide further evidence that PCB exposure limited to the early postnatal period and resulting in environmentally relevant body burdens produces long-term behavioral effects.