Effects of naltrexone,andd-amphetamine,and their interaction on the stimulus control of choice behavior of rats

The hypothesis that endogenous opioid peptides modulate attentional processes was tested. The effects of the opioid antagonist naltrexone (NALT),d-amphetamine (AMP), and their interaction were investigated in rats trained in a two-choice task in which the position of a short-duration light served as a cue for food-reinforced responses. NALT (0.25, 1.0, 5.0, and 10.0 mg/kg) produced no significant changes in performance (accuracy, choice latency, and food retrieval time). As predicted, AMP induced dose-dependent biphasic effects. Low doses of AMP (0.25 and 0.5 mg/kg) significantly enhanced accuracy, decreased choice latency, and lengthened food retrieval time; 1.25 mg/kg AMP disrupted accuracy, increased choice latency, and further lengthened food retrieval time. The combination of NALT (0.25, 1.0, and 10.0 mg/kg) and subthreshold doses of AMP (0.07 and 0.1 mg/kg) had no effect on performance except for an increase in food retrieval time with 10.0 mg/kg NALT, whereas the combination of NALT and moderate doses of AMP (0.5 and 1.0 mg/kg) disrupted accuracy, increased choice latencies, and lengthened food retrieval time. These results do not support the hypothesis that endogenous opioid peptides play a vital role in attentional processes or that opioid antagonists may be useful in the treatment of attentional deficit disorders.     

Effects of the potassium channel blockers, apamin and 4-aminopyridine, on scopolamine-induced deficits in the delayed matching to position task in rats: a comparison with the cholinesterase inhibitor E2020

 The effects of the muscarinic antagonists, scopolamine HBr and MeBr, a cholinesterase inhibitor, E2020, and K⁺ channel blockers, 4-aminopyridine (4-AP) and apamin, on the performance of rats in a delayed matching to position (DMTP) task were examined. The percentage of correct choices (choice accuracy), number of trials completed and intertrial intervals were measured. Discriminability and response bias were also calculated, using signal detection analysis. Scopolamine HBr (0.1 mg/kg), but not scopolamine MeBr (0.1 mg/kg), significantly and consistently reduced the choice accuracy and discriminability, but neither affected the other measurements. E2020 (0.03–1.0 mg/kg) had no effect on the baseline performance in the DMTP task, but at 1.0 mg/kg, it significantly attenuated the deficits in choice accuracy induced by scopolamine. 4-AP (0.001–0.1 mg/kg) had no effect on either baseline performance or deficits induced by scopolamine. Apamin (0.1–0.4 mg/kg) had no effect on choice accuracy and discriminability. Apamin also failed to attenuate the scopolamine-induced deficits. When administered in combination with scopolamine, apamin at 0.4 mg/kg significantly decreased the number of trials completed and increased the intertrial interval relative to that of the control group. Taken together, these results demonstrate that K⁺ channel blockers (4-AP and apamin), unlike a cholinesterase inhibitor (E2020), fail to reverse the scopolamine-induced deficits in the DMTP task. Received: 27 March 1997/Final version: 19 June 1997     

Additive deficits in the choice accuracy of rats in the delayed non-matching to position task after cholinolytics and serotonergic lesions are non-mnemonic in nature

The role of serotonin (5-HT) and its interaction with the muscarinic or nicotinic receptor-mediated mechanisms in the modulation of working memory and motor activity was investigated by assessing the effects of 5-HT lesion and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. A global serotonergic lesion was induced by the intracerebroventricular adminstration of 5,7-dihydroxytryptamine (5,7-DHT). Post-mortem neurochemical analysis revealed that serotonin and 5-hydroxyindoleacetic acid (5-HIAA) levels were reduced in frontal and parieto-occipital cortices and in hippocampi of 5,7-DHT lesioned rats. 5-HIAA levels were also reduced in striatum. 5,7-DHT lesion slightly impaired choice accuracy of rats in the DNMTP task and also transiently reduced motor activity in rats. Even the lower dose of scopolamine (0.075 mg/kg), a muscarinic receptor antagonist, impaired the choice accuracy already at the shortest delay (i.e. not indicative of a working memory impairment per se), and caused a marked disruption of motor activity (lengthened response latencies, increased probability of omissions and decreased trials completed). Furthermore, the quaternary analogue, N-methylscopolamine (0.150 mg/kg), affected the motor activity of rats to the same extent as scopolamine. Mecamylamine (1.0; 3.0 mg/kg) also interfered with motor activity and it slightly decreased the choice accuracy, which was not dependent on the delay. Although mecamylamine disrupted the performance of rats in the DNMTP task, the disruption was not as severe as that seen with scopolamine. Moreover, both scopolamine and mecamylamine augmented the slight impairment on the choice accuracy of 5,7-DHT lesioned rats, but this was non-mnemonic in character. We conclude that there is no evidence for any major interaction between the serotonergic system and muscarinic or nicotinic cholinergic mechanisms in working memory per se, but muscarinic and nicotinic receptor antagonists may act additively with the 5,7-DHT lesion to disrupt the choice accuracy of rats. Received: 22 November 1995 / Final version: 25 November 1996     

Discriminative stimulus properties of the benzodiazepine receptor antagonist flumazenil

Rats were trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor antagonist flumazenil using a conditioned taste aversion procedure. On drug trials, fluid-restricted rats were injected with flumazenil (32 mg/kg), given access to a 0.25% saccharin solution for 30 min, and injected with LiCl (1.8 mEq/kg IP). On saline trials, injections of saline bracketed the period of saccharin consumption. Acquisition of the discriminated taste aversion, as measured by differential effects of drinking between saline and drug trials, developed after only five pairings of flumazenil with the LiCl injections. Flumazenil did not alter saccharin consumption in unconditioned controls (N=9) that never received LiCl. The discrimination was also measured by flumazenil's ability to reduce the preference for saccharin over tap water using two-bottle choice tests. Flumazenil demonstrated dose-dependent generalization upon decreasing the training dose as low as 1 mg/kg. Two other BZ receptor antagonists of different chemical structure, CGS 8216 and ZK 93426, substituted completely for the flumazenil stimulus. Partial generalization was exhibited to the partial inverse agonists FG 7142 and beta-CCE, while the full inverse agonists DMCM and PTZ failed to substitute for the flumazenil stimulus. The BZ receptor agonists diazepam and alprazolam failed to substitute for the flumazenil stimulus, although partial generalization was shown with CDP. The results suggest that the BZ receptor antagonist flumazenil may produce intrinsic discriminative stimulus effects that are independent from those of BZ receptor agonists or inverse agonists.     

Effects of prior saline-morphine discrimination by pigeons on three-way discrimination including two morphine doses

The discriminative stimulus properties of morphine sulfate (MS) and their alteration by naltrexone (NTX) and d-amphetamine (AMP) challenges were examined in a quantitative dose 1, dose 2, and saline (SAL) drug discrimination task utilizing 1.8 mg/kg MS, 10 mg/kg MS, and SAL as discriminative stimuli under a fixed-ratio 30 schedule of food-maintained behavior in two groups of White Carneaux pigeons. Group A (Gp A) (n=6) subjects (Ss) were initially experimentally-and drug-naive, whereas group B Ss (n=4) were originally trained in a two-choice MS versus SAL discrimination task, and had a long behavioral and drug history. Significant differences were found in (1) number of sessions to criterion (STC) (group B greater than group A); (2) group A Ss generalized both NTX and AMP to SAL, whereas group, B Ss generalized AMP to the low dose (1.8 mg/kg) MS stimulus; and (3) in drug interaction test sessions, the high dose MS stimulus (10 mg/kg) in group A was unmodified by a range of challenge AMP doses (0.32 to 3.2 mg/kg). In contrast, group B Ss exhibited a shift to the low dose or SAL-appropriate keys when the same high dose MS stimulus was challenged by moderate doses of AMP. Group A and group B were similar in their pattern and distribution of responses when tested with various doses of MS, and also when challenge tests of the high dose MS stimulus were made with NTX. Qualitative generalization tests with the opiate agonist methadone suggested that methadone was more potent than MS in producing the discriminative stimulus properties learned under the MS stimulus conditions. It is suggested that the three-choice dose 1, dose 2, SAL discrimination procedure is a viable model to test agonist and antagonist relationships.     

Discriminative stimulus properties of valproic acid in the pigeon

Pigeons were successfully trained to discriminate 60 mg/kg valproic acid from saline using a two-key drug discrimination procedure. When 5–80 mg/kg doses of valproic acid were administered during generalization tests the percentage of responses directed to the valproic acid-appro-priate key varied directly with dose. the effects of administering the training dose of valproic acid at presession injection intervals ranging from 15 to 120 min were described by an inverted U-shaped function; the 30-min interval used during discrimination training engendered the largest percentage of valproic acid-appropriate responses. The discriminative stimulus properties of valproic acid failed to generalize to the anticonvulsant compounds phenobarbital (10, 20 mg/kg), phenytoin (2.5, 5 mg/kg), and ethosuximide (40, 80 mg/kg), indicating that not all anticonvulsant compounds share similar discriminative properties. Clonazepam (0.25, 0.50 mg/kg) and diazepam (1, 2 mg/kg), two benzodiazepines with anticonvulsant properties, produced quite different effects. The stimulus properties of valproic acid generalized to all doses of clonazepam, whereas intermediate generalization was evident with diazepam. Pentylenetetrazol (10, 20 mg/kg), chlorpromazine (5, 10 mg/kg), tripelennamine (2.5, 5.0 mg/kg), d-amphetamine (0.5, 1.0 mg/kg), morphine (1.25, 2.50 mg/kg), and imipramine (2.5, 5.0 mg/kg) induced only saline-like patterns of responding. The concomitant administration of pentylenetetrazol failed to antagonize the discriminative stimulus properties exerted by the training dose of valproic acid.     

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 level 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 drugdiscrimination task can be quantal in nature, and suggest that rats trained with PTZ, 20 mg/kg, are homogeneous in sensitivity to this stimulus. Offprint requests to: M.W. Emmett-Oglesby     

Effects of cocaine and d-amphetamine on sustained and selective attention in rats

The effects of cocaine and d-amphetamine were compared in two attention-loading tasks. Cued by the position of a light, rats were food-reinforced for pressing one of two levers in a 2-choice, discrete-trial procedure. In the "sustained attention" task, the cue light was illuminated for a brief period (1.8 sec or less) at the beginning of each trial. In the "selective attention" task, the cue light remained on until a level press, while a blinking light over the incorrect lever served as a distractor. In the sustained attention task, low doses of d-amphetamine (0.25 mg/kg SC) and cocaine (2.5 mg/kg SC) enhanced accuracy; some doses of d-amphetamine (0.75 mg/kg SC) and cocaine (1.25 and 2.5 mg/kg SC) also reduced choice latencies. In the selective attention task, the lower doses of these drugs had no effect on accuracy, the highest dose of d-amphetamine (1.25 mg/kg SC) disrupted accuracy, and all doses of the drugs reduced choice latencies. The time to retrieve food was increased in a dose-dependent fashion by both drugs in both tasks. These results indicate that, other than differences in potency, cocaine and d-amphetamine induce similar behavioral effects in attention-loading tasks, with improvement or interference with performance dependent on the dose and the type of attention demanded of the task.     

Permanent facilitation of avoidance behavior by d-amphetamine and scopolamine

Scopolamine (0.3, 0.6, 1.2, 2.4, 4.8 mg/kg) or d-amphetamine (0.25, 0.50, 1.00, 2.00, 4.00 mg/kg) was administered daily to independent groups of rats 30 min prior to training in a discriminated, Y-maze avoidance task. A dose-dependent relationship was found between amount of avoidance facilitation and drug dosage. Discontinuation of the drug following asymptotic performance resulted in a decrement in avoidance which varied as a function of the acquisition dosage. Results from a second experiment using the same task indicated that gradually reducing the dosage on consecutive training days rather than abruptly discontinuing the drug was more effective in producing permanent avoidance facilitation in the non-drug condition.     

A triazolam/amphetamine dose–effect interaction study: dissociation of effects on memory versus arousal

Rationale In addition to producing robust memory impairment, benzodiazepines also induce marked sedation. Thus, it is possible that the observed amnestic effects are secondary to more global sedative effects and do not reflect a specific primary benzodiazepine effect on memory mechanisms. Objective The objective was to use the nonspecific stimulant d-amphetamine to dissociate the sedative and memory-impairing effects of the benzodiazepine triazolam. Materials and methods Single oral doses of placebo, triazolam alone (0.25, 0.50 mg/70 kg), d-amphetamine sulfate alone (20, 30 mg/70 kg), and triazolam (0.25, 0.50 mg/70 kg) and d-amphetamine sulfate (20, 30 mg/70 kg) conjointly (at all dose combinations) were administered to 18 healthy adult participants across nine sessions in a double-blind, staggered-dosing, crossover design. In addition to standard data analyses, analyses were also conducted on z-score standardized data, enabling effects to be directly compared across measures. Results Relative to the sedative measures, the memory measures generally exhibited a pattern of less reversal of triazolam’s effects by d-amphetamine. The memory measures ranged in degree of reversal such that the most reversal was observed for reaction time on the n-back working memory task, and the least reversal was observed for accuracy on the Sternberg working memory task, with most measures showing an overall pattern of partial reversal. Conclusions Benzodiazepines have specific effects on memory that are not merely a by-product of the drugs’ sedative effects, and the degree to which sedative effects contribute to the amnestic effects varies as a function of the particular memory process being assessed.     

A verification of psychostimulant-induced improvement in sustained attention in rats: effects of d-amphetamine, nicotine, and pemoline

Previous studies from this laboratory have demonstrated that a variety of psychostimulant drugs can improve the performance of rats trained in a 2-choice stimulus detection task in which the correct responses are indicated by a briefly illuminated light. To enhance the construct validity of the task for assessing sustained attention, the procedure was modified so that the precue interval across trials varied unpredictably between 3, 7, and 11 s. After training rats (N = 17) so that their baseline accuracy levels stabilized between 75% and 88% correct, their performance was assessed after administration of d-amphetamine (0.125-0.75 mg/kg sc), nicotine (0.25-0.75 mg/kg sc), and pemoline (5.0-30.0 po). At certain doses all 3 drugs induced performance improvements in mean choice accuracy and choice response time. Because the precue intervals varied unpredictably and the cue durations used to maintain the rats' baseline accuracy levels were typically short (range = 70-500 ms), the task conforms to most conditions typically required for assessing sustained attention. Results verify the proposal that psychostimulant drugs can enhance the attentiveness of animals in a fashion similar to that documented in humans.     

Effects of drug-state change on discrimination performance

A single dose of d-amphetamine (0.25, 0.50, or 1.00 mg/kg), administered in 5 successive sessions, did not seriously impede the discrimination performance of male Holtzman rats under cued reinforcement conditions. A 2.00 mg/kg dose, however, produced a total cessation of operant behavior. In 2 postdrug (saline) sessions, groups previously treated with 0.50 or 1.00 mg/kg demonstrated an initial decrement and subsequent recovery in performance. A second experiment demonstrated that rats administered either saline or 0.50 mg/kg d-amphetamine for 5 successive sessions showed a decrement and subsequent recovery in performance when switched to the opposite treatment condition for the next 2 sessions. These data may be explained in terms of a change in drug state.     

Activation of 5-HT2A receptors impairs response control of rats in a five-choice serial reaction time task

The present experiments investigated the effects of agents acting at serotonin (5-HT)-2 receptors on the performance of rats in a choice serial reaction time (5-CSRT) task in order to examine the role of 5-HT2 receptors in the modulation of attention and response control. The results indicate that DOI, [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride; 0.05, 0.1 and 0.2 mg/kg, subcutaneously], a 5-HT(2A/2C) agonist, slightly impaired the choice accuracy of the well performing rats and markedly increased their premature responding. DOI (0.05 and 0.1 mg/kg) had no effect on the latency to collect earned food pellets or to respond correctly, indicating that these lower doses of DOI did not reduce motivation for the food reward in this task. The selective effect of a low dose of DOI (0.1 mg/kg) on premature responding was completely blocked by ketanserin (0.2 mg/kg), a 5-HT2A antagonist, and ritanserin (0.3 mg/kg), a 5-HT(2A/2C) antagonist, but only partially blocked by a high dose of SER082 (1.0 mg/kg), a 5-HT2C antagonist. In contrast to DOI, mCPP, [1-(3-phenyl)piperazine; 0.05 and 0.15 mg/kg], a 5-HT2C agonist, had no effect on choice accuracy or premature responding, but it reduced behavioral activity and/or arousal as indicated by the decreased number of trials completed and increased the probability of omissions. SER082 (1.0 mg/kg) blocked the effects of mCPP on performance. These data suggest that the overactivation of 5-HT2A receptors impairs response control in a 5-CSRT task, whereas the overactivation of 5-HT2C receptors can affect behavioral activity and/or arousal state of the animals for this food rewarded task.     

A comparison of the effects of the novel muscarinic receptor agonists L-689,660 and AF102B in tests of reference and working memory

Four experiments compared the CNS effects of a novel M₁/M₃ receptor agonist L-689,660 with those of the M₁/M₃ muscarinic receptor agonist AF102B. In the mouse tail-flick test of antinociception (TF) the minimum effective doses to increase tail-flick latency (MED) of L-689,660 and AF102B were 0.03 mg/kg and 10.0 mg/kg, respectively. In a rat conditioned-suppression-of-drinking (CSD) test of reference memory, doses of 0.3 and 1.0 mg/kg L-689,660 and a dose of 5.0 mg/kg AF102B reversed a scopolamine-induced deficit in performance (0.6 mg/kg). Although there was a tendency for L-689,660 to reverse the scopolamine-induced (0.4 mg/kg) performance deficit in a rat delayed-matching-to-position (DMTP) test, the difference failed to reach statistical significance. In contrast, a 5.0 mg/kg dose of AF102B potentiated the scopolamine-induced deficit in choice accuracy and the number of trials completed on this task. In a response sensitivity (RS) test, chain-pulling rates were significantly decreased by L-689,660 (MED=0.03 mg/kg) and by AF102B (MED=5.0 mg/kg). These results suggest that L-689,660 and AF102B may ameliorate or reverse a scopolamine-induced deficit, but only at doses that also reduce chain-pulling rates on operant schedules of reinforcement.     

Effects of anticholinergics on serial-probe recognition accuracy of rhesus macaques (Macaca mulatta)

Potential deleterious behavioral effects of the anticholinergics biperiden and scopolamine were examined via the performance of rhesus monkeys on a serial-probe recognition (SPR) procedure. On each trial, six unique stimuli (list items) were presented sequentially followed by a choice phase. In the choice phase, two stimuli were presented, a standard or 'default' stimulus (a white rectangle) and a 'probe' stimulus that differed with each choice trial. Choosing the probe stimulus was considered correct if the probe matched one of the list items; otherwise, choosing the default stimulus was considered correct. Behavior was examined under a range of doses of biperiden (0.001-1.0 mg/kg) and scopolamine (0.0056-0.03 mg/kg). Scopolamine (0.01-0.03 mg/kg) and biperiden (0.3-1.0 mg/kg) reduced overall accuracy. At the highest dose, scopolamine, but not biperiden, reduced the number of trials completed per session. The results suggest that doses of scopolamine and biperiden necessary to prevent or eliminate organophosphate induced seizures may affect performance adversely. However, because the degree of impairment from biperiden was modest, further examination of this anticonvulsant may be warranted.     

Failure of pimozide to disrupt the acquisition of light-dark and spatial discrimination problems

The effects of pimozide, a dopamine (DA) receptor blocker, on associative learning was examined using two appetitively motivated choice paradigms. In Experiment I, low to moderate doses of pimozide (0.125, 0.25 mg/kg) were not found to disrupt the acquisition of a two bar simultaneous discrimination task. However, with continued testing, progressive deficits in response accuracy were observed in rats pretreated with 0.25 mg/kg pimozide. When subsequently tested drug-free these animals demonstrated a rapid and marked improvement in performance. Experiment II used a spatial discrimination task (T-maze) requiring a natural response (running) with minimal response demands (short stem and arms). Rats pretreated with 0.25, 0.50, and 1.0 mg/kg pimozide showed comparable levels of acquisition and maintained discriminated performance relative to vehicle controls. Similar results were obtained when the reinforced (S+) and nonreinforced (S-) stimuli were reversed. Moreover, animals receiving 2.0 mg/kg pimozide and not rendered cataleptic also demonstrated acquisition of both the initial discrimination and its reversal. It was concluded that rats pretreated with pimozide are able to acquire the significance of environmental stimuli and direct their responding accordingly if they are motorically capable of emitting the required response.     

Effects of nimodipine on the discriminative stimulus properties ofd-amphetamine in rats

The discriminative stimulus (DS) properties ofd-amphetamine (AMP) are thought to be mediated by enhanced release of catecholamines, which may involve neuronal calcium influx through voltage sensitive channels. The present study examined the influence of nimodipine, a calcium channel blocker, on the DS properties of AMP. Rats (N=8) were trained to discriminate AMP (0.5 mg/kg, IP) from saline in a two-lever, food-reinforced, drug discrimination paradigm. Nimodipine alone (2.0–5.6 mg/kg, IP) did not substitute for AMP. When given in combination with AMP, 2.0 mg/kg nimodipine increased by less than 2-fold the AMP dose necessary to induce AMP-appropriate responses. Higher doses of nimodipine combined with AMP did not increase the magnitude of this effect. Nimodipine enhanced the effects of AMP on response rate. Haloperidol (0.125 mg/kg) increased by approximately 4-fold, whereas diazepam (0.5 or 1.0 mg/kg) and morphine (5.0 mg/kg) increased by approximately 2-fold the AMP dose necessary to induce AMP-appropriate responses. The interaction with AMP was associated with enhanced reduction of response rate in the tests with diazepam and morphine but not haloperidol. These results suggest that nimodipine attenuates the DS properties of AMP, probably in a non-specific way, due to the ability of nimodipine itself to induce a discriminable internal state.     

Discriminative stimulus properties of d-amphetamine in pigeons

Two out of four pigeons were successfully trained in an operant procedure to discriminate between the presence and absence of the effects induced by d-amphetamine (final dose: 1.6 mg/kg). The solvent (saline) or d-amphetamine was administered intramuscularly (IM) 30 min prior to training. Tests with other drugs and dosages indicated that l-amphetamine (ED50 = 0.55 mg/kg) and cocaine (ED50 = 1.05 mg/kg) fully generalized to d-amphetamine (ED50 = 0.35 mg/kg), whereas drugs such as p-hydroxy-amphetamine (1.6 and 3.2 mg/kg), morphine (1.5, 3.0 and, 6.0 mg/kg), and delta 9-THC (0.125, 0.25, and 0.50 mg/kg) failed to do so at the doses tested. Apomorphine (0.25 and 0.50 mg/kg) and LSD-25 (0.04 and 0.08 mg/kg) produced intermediate results. Pretreatment with haloperidol (dose range: 0.04 to 1.28 mg/kg), but not propranolol (10 and 20 mg/kg), attenuated significantly the d-amphetamine (1.6 mg/kg) stimulus effects. The two pigeons emitted predominantly d-amphetamine appropriate responses when the training dose (1.6 mg/kg) of d-amphetamine was tested on different occasions 15, 60, and 120 min after the administrations. One bird emitted mostly vehicle appropriate responses when tested 240 min after the d-amphetamine injection whereas the other bird performed d-amphetamine appropriate responses. Selection of the non-drug associated key occurred in the two birds when testing was carried out 480 min (8 hrs) after the administration of d-amphetamine.     

Similarities between the stimulus properties of phenylpropanolamine and amphetamine

Rats at 80% body weight were trained to discriminate 1.0 mg/kg d-amphetamine versus saline in a two-lever, discrete trial drug discrimination task to obtain food pellets. After reliable discriminative control of lever choice was established, various doses of d,l-phenylpropanolamine (PPA, i.e., d,l-norephedrine) were substituted for the amphetamine training dose in non-reinforced test trials. Test doses of 10, 20, and 40 mg/kg PPA resulted in over 90% responses on the amphetamine-appropriate lever. Lower doses (1.25, 2.5, and 5.0 mg/kg) resulted in predominantly saline-appropriate responses. The generalization seen after the 20 mg/kg dose of phenylpropanolamine was blocked by pretreatment with 0.5 mg/kg haloperidol, suggesting that the generalization from amphetamine to PPA was mediated by a dopaminergic mechanism.     

Disruptive effects of muscimol infused into the basal forebrain on conditional discrimination and visual attention: differential interactions with cholinergic mechanisms

The behavioural effects of GABAergic manipulation of the basal forebrain were investigated using two behavioural tasks, which previous studies have shown to yield dissociable effects following quisqualate-induced lesions of the basal forebrain: a five-choice serial reaction time task, involving approaching the location of a brief visual stimulus that is associated with reward; and a conditional visual discrimination task, requiring retrieval of information about a discriminative stimulus that stays constant over time. Following acquisition of the tasks, chronic guide cannulae were stereotaxically implanted into the basal forebrain. Those animals trained on the conditional visual discrimination task showed a dose-dependent reduction in choice accuracy and a lengthening of latency to respond correctly to the visual stimulus following administration of the GABA-A agonist, muscimol (1, 2, 3 ng/µl/hem). While certain of these deficits, for example response latency, could be restored to control levels by co-administration of the GABA-A antagonist, bicuculline, none of the behavioural impairments could be significantly attenuated by systemic co-administration of the cholinesterase inhibitor, physostigmine (0.05, 0.1, 0.2 mg/kg, IP). Similarly, a dose dependent effect of muscimol (1, 1.5, 2 ng/µl/hem) on choice accuracy and correct response latency was observed on performance of the five-choice attentional task. However, in contrast to the conditional task, significant attenuation of the impairment in choice accuracy was obtained following administration of physostigmine (0.05 and 0.1 mg/kg). Attenuation of muscimol-induced deficits by administration of bicuculline was also observed. It is therefore evident that although manipulation of GABAergic activity in the region of the basal forebrain produces profound deficits in different tasks of cognitive function, only some of these may be due to modulation of the magnocellular cholinergic projection to the neocortex.