Opposite Lever Research Articles

Культура академічної доброчесності PhD-здобувачів: досвід Латинської Америки

The article deals with the features of higher education of the third level in Latin America, namely Brazil and Mexico. The object of the research is the quality system of higher education in Latin America (Brazil and Mexico), and its subject is the formation and attitude to the culture of academic integrity of PhD-applicants in these countries. The goal is highlighting the implementation of the leading practices for the formation of the academic integrity culture among PhD-applicants in Latin America, in particular Brazil and Mexico. Objectives are to consider ways of forming the academic integrity culture of PhD-applicants at the international, state and institutional levels in Latin America, in particular Brazil and Mexico. It has been investigated that scientific activity is widely developed in Brazil, and the basis for the formation of academic integrity is used according to the experience of the United States of America. However, violations such as plagiarism or deception are perceived not as a manifestation of unethical behaviour, but more as a violation of ignorance or unintentional borrowing. There is also a low level of success of applicants for higher education, which is also fruitful for the generation of dishonest behaviour. Mexico is the «opposite lever» in the experience of the academic integrity culture, since the economic system of the country has its own gaps and leads to a high level of corruption, and as a result, the manifestation of academic dishonesty in all its forms. Despite this, the country understands the need to form the academic integrity culture as a factor influencing the further responsible and ethical activities of a future competitive specialist. Thus, there is a cyclical nature: the honest behaviour of the applicant for education forms the skills of the honest behaviour of a specialist, the honest behaviour of a specialist is the absence of corruption, in particular in education.

D-Cycloserine Facilitates Reversal in an Animal Model of Post-traumatic Stress Disorder

Many psychiatric disorders are associated with cognitive dysfunction that is ineffectively treated by existing pharmacotherapies and which may contribute to poor real-world functioning. D-cycloserine (DCS) is a partial N-methyl-D-aspartate (NMDA) agonist that has attracted attention because of its cognitive enhancing properties, including in people with post-traumatic stress disorder (PTSD). Here, we examined the effect of DCS on reversal learning - a type of cognitive flexibility – following exposure to single prolonged stress (SPS), a rodent model of PTSD. Male Sprague Dawley rats (n = 64) were trained to press levers in an operant chamber, matched for performance and assigned to SPS or control (unstressed) groups. Following SPS, rats received three additional lever press sessions, followed by a side bias test on day three. One day later they learned a response discrimination rule (press left or right lever, opposite to side bias) and on a subsequent day were trained (and tested) for reversal to the opposite lever. DCS (15 mg/kg) or vehicle was administered 30 minutes prior to the reversal session. No between-group differences were found in acquisition or retrieval of the initial rule, but a significant drug x stress interaction on response discrimination reversal indicated that DCS had a greater beneficial effect on SPS rats’ cognitive flexibility than it did on performance in controls. These findings add to a growing literature on the beneficial effects of DCS for treating a wide variety of deficits that develop following exposure to extreme stress and may have implications for the development of novel pharmacotherapies for PTSD.

P.1.h.012 - Chronic memantine treatment prevents short-term memory impairment caused by conjoint immunolesions of GABAergic and cholinergic medial septal neurons in rats

NMDA glutamatergic and GABAergic transmission have both been implicated in regulating working memory functions mediated by the prefrontal cortex (PFC), and perturbations in these neurotransmitter systems have been proposed to underlie deficits in these functions observed in schizophrenia. Here, we examined the consequence of disrupting GABAergic or NMDA glutamatergic transmission within the medial PFC of rats on a delayed-response paradigm with translational relevance to working memory tasks used with humans. The operant delayed non-match to position task consisted of a sample phase (one lever extended) and a choice phase wherein rats were required to choose the opposite lever, separated by a variable delay (1–24 s). In well-trained rats, inactivation of the PFC via infusions of GABA agonists baclofen/muscimol (100 ng each) induced delay-independent deficits. Reducing PFC GABA transmission with the GABA-A receptor antagonist bicuculline (12.5–50 ng) also caused delay-independent impairments and increased trial omissions and response latencies during the sample and end-of-delay phases. On the other hand, non-selective blockade of PFC NMDA receptors with MK-801 (3–6 μg) disrupted performance, but these effects more closely resembled delay-dependent impairments. However, selective blockade of GluN2B-containing NMDA receptors with Ro-25-6981 (2.5 μg) did not affect any measures of performance. These results demonstrate that both intact PFC GABA and NMDA receptor signalling are integral for accurate delayed-responding, although they may differentially regulate encoding vs maintenance of information within working memory. Furthermore they suggest that perturbations of both of these neurochemical signals within the PFC may contribute differentially to impairments in working memory observed in schizophrenia.

Prefrontal cortical GABAergic and NMDA glutamatergic regulation of delayed responding

NMDA glutamatergic and GABAergic transmission have both been implicated in regulating working memory functions mediated by the prefrontal cortex (PFC), and perturbations in these neurotransmitter systems have been proposed to underlie deficits in these functions observed in schizophrenia. Here, we examined the consequence of disrupting GABAergic or NMDA glutamatergic transmission within the medial PFC of rats on a delayed-response paradigm with translational relevance to working memory tasks used with humans. The operant delayed non-match to position task consisted of a sample phase (one lever extended) and a choice phase wherein rats were required to choose the opposite lever, separated by a variable delay (1–24 s). In well-trained rats, inactivation of the PFC via infusions of GABA agonists baclofen/muscimol (100 ng each) induced delay-independent deficits. Reducing PFC GABA transmission with the GABA-A receptor antagonist bicuculline (12.5–50 ng) also caused delay-independent impairments and increased trial omissions and response latencies during the sample and end-of-delay phases. On the other hand, non-selective blockade of PFC NMDA receptors with MK-801 (3–6 μg) disrupted performance, but these effects more closely resembled delay-dependent impairments. However, selective blockade of GluN2B-containing NMDA receptors with Ro-25-6981 (2.5 μg) did not affect any measures of performance. These results demonstrate that both intact PFC GABA and NMDA receptor signalling are integral for accurate delayed-responding, although they may differentially regulate encoding vs maintenance of information within working memory. Furthermore they suggest that perturbations of both of these neurochemical signals within the PFC may contribute differentially to impairments in working memory observed in schizophrenia.

Anabolic–androgenic steroids impair set-shifting and reversal learning in male rats

Anabolic–androgenic steroid (AAS) abuse is prevalent not only among elite athletes, but is increasingly common in high school and collegiate sports. AAS are implicated in maladaptive behaviors such as increased aggression and risk taking, which may result from impaired cognition. Because they affect dopamine function in prefrontal cortical (PFC)-striatal circuitry, AAS may disrupt PFC-dependent processes such as behavioral flexibility. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5mg/kg in water with 13% cyclodextrin) or vehicle sc, and tested for set-shifting and reversal-learning. For set-shifting, rats were trained on a visual cue task (VCT), then were shifted to a direction cue task (DCT), or vice-versa. For reversal learning, rats were first trained on VCT and were then required to press the opposite lever. 2-cue set-shifting introduced a novel paradigm in which rats shifted from a 1-Light Visual Task (1LVT) to a tone cue task (TCT). Testosterone-treated rats were significantly impaired on the set-shift from DCT to VCT compared to vehicle-treated controls (trials to criterion: vehicle 240.9±29.9, testosterone 388.3±59.3, p<0.05). However, on the set-shift from VCT to DCT, testosterone did not affect performance. During reversal-learning, testosterone significantly increased trials to criterion (vehicle: 495.9±91.8 trials, testosterone: 793.7±96.7 trials, p<0.05). In 2-cue set-shifting, testosterone diminished performance and the difference showed borderline significance (vehicle: 443.2±84.4 trials, testosterone: 800.4±178.2 trials, p=0.09). Our results show that testosterone impairs behavioral flexibility and have implications for understanding cognitive and behavioral changes in human AAS users.

Reproductive experience does not persistently alter prefrontal cortical-dependent learning but does alter strategy use dependent on estrous phase

Reproductive experiences in females comprise substantial hormonal and experiential changes and can exert long lasting changes in cognitive function, stress physiology, and brain plasticity. The goal of this research was to determine whether prior reproductive experience could alter a prefrontal–cortical dependent form of learning (strategy set shifting) in an operant box. In this study, female Sprague–Dawley rats were mated and mothered once or twice to produce either primiparous or biparous dams, respectively. Age-matched nulliparous controls (reproductively-naïve females with no exposure to pup cues) were also used. Maternal behaviors were also assessed to determine whether these factors would predict cognitive flexibility. For strategy set shifting, rats were trained in a visual-cue discrimination task on the first day and on the following day, were required to switch to a response strategy to obtain a reward. We also investigated a simpler form of behavioral flexibility (reversal learning) in which rats were trained to press a lever on one side of the box the first day, and on the following day, were required to press the opposite lever to obtain a reward. Estrous phase was determined daily after testing. Neither parity nor estrous phase altered total errors or trials to reach criterion in either the set-shifting or reversal-learning tasks, suggesting that PFC-dependent cognitive performance remains largely stable after 1 or 2 reproductive experiences. However, parity and estrous phase interacted to alter the frequency of particular error types, with biparous rats in estrus committing more perseverative but fewer regressive errors during the set-shifting task. This suggests that parity and estrous phase interfere with the ability to disengage from a previously used, but no longer relevant strategy. These data also suggest that parity alters the behavioral sensitivity to ovarian hormones without changing overall performance.

Blockade of NMDA GluN2B receptors selectively impairs behavioral flexibility but not initial discrimination learning

Behavioral flexibility is the ability to adjust behavior when environmental contingencies change and is compromised in disease states such as schizophrenia, attention deficit hyperactivity disorder, and following damage to the prefrontal cortex. The present study investigated the contribution of N-methyl-D-aspartate GluN2B receptor subunits in the initial learning and in shifting between or within discrimination strategies (i.e., strategy set-shifting and reversal learning), using tasks conducted in operant chambers. Strategy set-shifting required rats initially to learn a visual-cue discrimination (day 1) and on day 2, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were trained on a response discrimination on day 1 and then required to select the opposite lever on day 2. Blockade of GluN2B receptors with systemic administration of Ro25-6981 on day 1 did not impair initial acquisition of either a response or visual-cue discrimination nor did these treatments affect performance of strategy or reversal shifts on day 2. However, administration of Ro25-6981 prior to a set-shift or reversal on day 2 significantly impaired performance on both tasks, inducing a selective increase in perseverative errors, indicative of a disruption the ability to suppress a previously acquired prepotent response. These data suggest that systemic blockade of GluN2B receptors Ro25-6981 does not appear to interfere with the initial acquisition of simple visual or response discriminations. However, these receptors do appear to play a central and selective role in the modification of previously acquired strategies or stimulus-reward associations, facilitating behavioral inhibition so that novel patterns of behavior may emerge.

Ventral Striatal Dopamine Modulation of Different Forms of Behavioral Flexibility

Different forms of behavioral flexibility are facilitated by interactions between separate regions of the prefrontal cortex and their striatal outputs. However, the contribution of ventral striatal dopamine (DA) to these functions is unclear. The present study assessed the involvement of DA receptors in the nucleus accumbens (NAc) core on either between- or within-strategy shifts using operant chamber-based tasks. Strategy set-shifting required rats initially to learn a visual-cue discrimination and, on the following day, shift to using an egocentric spatial response strategy to obtain reward. For reversal learning, rats were initially trained on a response discrimination and then required to select the opposite lever to receive food reward. Intra-NAc microinfusions of D(1) (SCH23390) but not D(2) (eticlopride) receptor antagonists impaired set-shifting, disrupting the maintenance of a new strategy. Conversely, supranormal activation of D(2) (quinpirole) but not D(1) (SKF81297) receptors also impaired set-shifting, inducing perseverative deficits. However, only infusions of the D(2) agonist impaired reversal learning, but did so without disrupting initial response learning. Thus, mesoaccumbens DA, acting on D(1) receptors, selectively facilitates complex forms of flexibility requiring shifts between different strategies, but does not appear to contribute to simpler forms of flexibility entailing shifts of specific stimulus-reward associations. In contrast, abnormal increases in D(2) receptor activity cause a more general impairment in behavioral flexibility. These findings suggest that deficits in these forms of executive functioning observed in disorders linked to dysfunction of the DA system may be attributable in part to aberrant increases or decreases in mesoaccumbens DA activity.

Memory and Perseveration on a Win-Stay, Lose-Shift Task in Rats Exposed Neonatally to Alcohol

It is important to understand the relationship between perseverative responding resulting from perinatal exposure to alcohol and potential underlying causes, including attention, memory, or response-inhibition problems. The present study was designed to examine the relationship between perseveration and memory. Rats exposed neonatally to 6 g/kg/day alcohol from postnatal day (PD) 4 through PD 9 using an artificial rearing technique (n = 8) were compared with an artificially reared gastrostomy control group (n = 8) and a suckle control group (n = 8). Activity levels were assessed from PD 18-21. Beginning on PD 45, subjects were deprived of food and responded for food on a two-lever win-stay, lose-shift task in which reinforcement probability was a function of reinforcement delivery on the previous trial. If reinforcement was delivered, only a response on the same lever (stay) was reinforced. If reinforcement was not delivered, only a response on the opposite lever (shift) was reinforced. Effective responding depended on subjects remembering whether a reinforcer was delivered on the preceding trial. The intertrial interval varied across conditions (5 seconds or 60 seconds). Alcohol-exposed rats showed increased activity during activity testing but did not differ from controls on win-stay, lose-shift accuracy. All groups showed a performance decrease at longer intertrial intervals. Alcohol-exposed rats showed increased lever pressing during the intertrial interval compared with suckle control rats but not with gastrostomy control rats. Choice behavior was comparable for all groups on the win-stay, lose-shift task, indicating that memory, as assessed by this task, was not differentially affected by alcohol exposure. Alcohol-exposed rats responded more during the intertrial interval compared with suckle controls, suggesting increased activity without increased response inhibition. The win-stay, lose-shift procedure is a potentially useful tool for separating simple activity level effects, memory-related effects, and response-inhibition effects. This study also highlights the need for additional research describing the relationship between perseverative responding and underlying mechanisms.

Discriminative stimulus properties of ethoxy idazoxan

The technique of drug discrimination was used to examine the ability of the highly selective α(2)-adrenoceptor antagonist ethoxy idazoxan, which has negligible affinity for α( 1)-adrenoceptors or I(2) imidazoline receptors, to produce an interoceptive discriminable stimulus or cue in rats. Rats were trained to respond on one lever after receiving α-ethoxy idazoxan (2.5 mg/kg, i.p.) and on the opposite lever after saline vehicle. The ethoxy idazoxan cue appeared to be mediated by antagonists of central α(2)-adrenoceptors, on the basis that dose- related substitution was produced by the highly selective α(2)-adrenoceptor antagonists idazoxan (imidazoline), fluparoxan and 1-(2-pyrimidinyl) piperazine (1-PP) (both non-imidazoline) but not by clonidine, which acts as an agonist at this receptor, nor by the peripherally acting α(2)-adrenoceptor antagonist L659,066. However, the α(2)-adrenoceptor antagonists yohimbine and atipamezole showed partial and non-dose-dependent substitution for ethoxy idazoxan over a wide range of doses. 2-BFI [2-(2-benzfuranyl)-2-imidazoline, RX801077], an imidazoline which is highly selective for I(2) imidazoline receptors over α(2)-adrenoceptors, showed dose- dependent substitution for ethoxy idazoxan, although the maximum effect (73% responding on the ethoxy idazoxan lever) fell short of criteria adopted for full substitution. Among other agents which bind to I(2) receptors, only idazoxan and 2-phenyl-2-imidazoline exhibited significant substitution; cirazoline could only be tested at very low doses because it powerfully inhibited responding in general, probably due to its α(1)-adrenoceptor agonist properties. It is suggested that the ability of 2-BFI to substitute partially for ethoxy idazoxan might be due to the ability of both agents to increase extracellular concentrations of noradrenaline.

Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands

An operant task for the measurement of sustained attention or vigilance in rats was characterized. The task requires the animals to respond to the presentation of visual signals (presented for 25, 50, or 500 ms) by operating one lever ("hits") and to the absence of a signal by operating the opposite lever ("correct rejection"). Incorrect responses ("misses" and "false alarms", respectively) were not rewarded. Performance in this task is a function of signal length, i.e., the shorter the signals the higher the number of misses. An increase in "background noise" by flashing the chamber houselight (at 0.5 Hz) impaired the animals' ability to discriminate between signal and non-signal events. Also flashing the houselight augmented the vigilance decrement observed for shortest signals. An increase in the event-rate also resulted in a vigilance decrement. Finally, the inability of the animals to time signals was examined by testing the effects of an increase in event asynchrony. In a second experiment, the performance of differently aged rats (6- and 20 month-old male BNNia/F344 rats) was studied. Compared to young animals, 20-month-old rats showed a decrease in their ability to discriminate between shortest signals (25 ms) and non-signal events but did not differ in their ability to correctly reject non-signal trials. Administration of the benzodiazepine receptor (BZR) agonist chlordiazepoxide (CDP; 3, 5, 8 mg/kg) resulted in an impairment of the animals' ability to discriminate between signal and non-signal events and, similar to the effects of age, this effect was exclusively due to an increase in the number of misses. CDP generally produced potent effects while affecting the aged animals to a greater degree. BZR-ligands with weak or "selective" inverse agonist properties (ZK 93426; beta-CCtB) did not affect vigilance performance. The BZR partial inverse agonist RU 33965 (0.1, 0.5 mg/kg) dose-dependently impaired vigilance performance. The administration of amphetamine (0.4, 0.8 mg/kg) also impaired performance, but these impairments were possibly based on effects unrelated to attentional mechanisms. The finding that performance in this task revealed the interactions between the effects of age and BZR agonists on attentional abilities further supports the validity of measures of performance generated by this task.

Effects of CGS 19755 and dizocilpine (MK 801) on delayed time discrimination performance

The effects of the competitive NMDA (N-methyl-D-aspartate) receptor antagonist CGS 19755 and the non-competitive NMDA receptor antagonist dizocilpine (MK 801) on time discrimination and short-term memory were investigated in rats trained on a delayed time discrimination task. In a two-lever operant chamber, pressing one lever was correct and reinforced with a food pellet after presentation of a stimulus light for 2 s (SD(short)); pressing the opposite lever was correct after presentation of a stimulus light for 8 s (SD(long)). CGS 19755 (3.0 mg/kg) attenuated performance, decreased nose-pokes (an activity necessary to trigger the presentation of the discriminative stimulus and the presentation of the response levers), and increased response latencies (time from 'opportunity to leverpress' to 'actual leverpress'). The highest dose of dizocilpine (0.2 mg/kg) tested also attenuated performance. Further, the number of nose-pokes and response latencies were not altered by any dose of dizocilpine. With increasing delays, saline-injected animals developed a bias towards reporting an occurrence of an SD(long), independent of the actual stimulus presented. This bias was attenuated or even reversed by CGS 19755 (3.0 mg/kg) and (0.2 mg/kg). Our results suggest that NMDA receptors are directly or indirectly involved in time discrimination performance.

Force-velocity relation in paired frog sartorius muscles attached to opposite lever arms.

To study the mechanism of the longitudinal stability at the level of whole muscles, paired frog sartorius muscles were attached to the opposite lever arms at unequal distances from the pivot. The lever was initially fixed in position, and when the full isometric forces were developed in both muscles, it was released to move, the result being that the advantaged muscle shortened by stretching the disadvantaged one with a nearly constant velocity depending on the ratio between their points of attachment from the pivot. The force-velocity relation of the advantaged muscle was virtually identical with the ordinary force-velocity relation obtained from the isotonic release experiments, while the force-velocity relation of the disadvantaged muscle was found to be entirely different from the ordinary one because of a marked increase in the load-bearing ability. These results are discussed in connection with the enhancement of mechanical performance in lengthening muscle.

The discriminative stimulus properties of LSD: Mechanisms of action

The CNS correlates of d-lysergic acid diethylamide (LSD) actions were investigated by means of a sensitive and specific behavioural assay procedure. Rats were trained to discriminate D-LSD from saline in two lever operant chambers. After intraperitoneal injections of 0.08 mg/kg of LSD, reinforcement could be obtained only by responding on one particular lever (left or right); responding on the opposite lever was reinforced only after saline injections. Once the LSD and saline exerted reliable stimulus control over lever choice (85% correct), rats were tested with various agents which alter the functional activity of the transmitter-containing neuronal systems. l-Tryptophan, chlorimipramine and fluoxetine, all of which increase the synaptic availability of serotonin, neither blocked nor, by themselves, mimicked (transferred to) LSD. However, quipazine, a putative serotonin agonist, produced an almost complete (78%) transfer to LSD. The presumed serotonin antagonists: methiothepin, 2-bromo-D-lysergic acid diethylamide, methysergide, cyproheptadine and cinanserin, blocked the LSD cue in a dose-related manner. The potent dopamine antagonists: haloperidol, fluphenazine, trifluoperazine, α-flupenthixol, and (+)-butaclamol, were without effect on the discriminability of LSD as were α- and β-adrenergic, cholinergic and histaminergic antagonists. Apomorphine, a dopamine agonist, produced a partial transfer to LSD. These data indicate that the discriminative stimulus properties of LSD may be mediated by post-synaptic serotonin or LSD receptors. Dopamine receptors did not seem to be involved in the LSD stimulus cue.

Pentazocine, cyclazocine, and nalorphine as discriminative stimuli

Pentazocine, cyclazocine, and nalorphine are narcotic antagonists that also have analgesic activity of their own. The present investigation compared the stimulus properties of these three drugs in rats. Each drug was used as a discriminative stimulus for a separate group of rats. Depression of one lever resulted in food reinforcement following the administration of drug, and the opposite lever was reinforced after saline. Each drug readily acquired control of discriminated responding. The specific narcotic antagonist, naloxone, which antagonizes many of the effects of pentazocine, cyclazocine, and nalorphine, also antagonized the discrimination of these drugs. Stimulus generalization tests to each other narcotic antagonist, d-amphetamine, morphine, and LSD, showed that each narcotic antagonist has highly specific stimulus properties. Clear generalization occurred only to pentazocine and cyclazocine in the nalorphine-saline group, but neither cyclazocine nor pentazocine generalized to nalorphine.

Generalization of morphine and lysergic acid diethylamide (LSD) stimulus properties to narcotic analgesics.

The present investigation sought to determine whether the stimulus properties of morphine and lysergic acid diethylamide (LSD) would generalize to several narcotic analgesics which vary in their subjective effects. Morphine and saline served as discriminative stimuli for one group of rats in a 2-lever discrimination task. LSD and saline were discriminative stimuli for a second group. Depression of one lever in an operant chamber resulted in reinforcement following the administration of morphine or LSD and the opposite lever was reinforced after saline. After discriminated responding was stable, stimulus generalization tests with narcotic analgesics and antagonists showed that the stimulus properties of morphine generalized to methadone and meperidine, and partially to pentazocine, all of which produce morphine-like subjective effects in humans. Morphine stimulus properties did not generalize to nalorphine or cyclazocine, which produce dissimilar subjective effects. The stimulus properties of LSD generalized partially to cyclazocine, but not to nalorphine. In humans cyclazocine and nalorphine produce a high incidence of psychotomimetic effects, but the subjective effects of cyclazocine are differentiable from those of LSD.

A comparison of the stimulus effects of morphine and lysergic acid diethylamide (LSD)

Morphine and lysergic acid diethylamide (LSD) each was used as a discriminative stimulus for rats. After the injection of drug (morphine or LSD), depression of one lever of an operant test chamber resulted in positive reinforcement according to a variable interval schedule of 15 sec (VI-15 sec). When saline was given, responses on the opposite lever were reinforced. Discriminated responding occurred when either morphine or LSD served as the discriminative stimulus. When animals which were trained to d discriminate morphine from saline were given LSD, they pressed predominantly the saline-correct lever. Similarly, LSD discrimination did not generalize to morphine. Two 5-hydroxytryptamine (5-HT) antagonists, cyproheptadine and methysergide, and one acetylcholine (Ach) antagonist, atropine, did not effect morphine or LSD discrimination. The narcotic antagonist, naloxone, blocked the stimulus effect of morphine, but did not alter LSD discrimination. These results indicate that the morphine and LSD stimuli are dissimilar and that the integrity of 5-HT or Ach nervous systems is not essential for morphine or LSD to serve as a discriminative stimulus.

Studies on the time course and the effect of cholinergic and adrenergic receptor blockers on the stimulus effect of nicotine.

This study investigated the stimulus property of nicotine in the rat. The primary objectives of the study were 1. to determine the time course of the nicotine stimulus and its relationship to brain levels of the drug and 2. to determine whether the nicotine stimulus is dependent upon the integrity of specific neurotransmitter systems. A lever choice discrimination was used. After injection of nicotine, depression of one lever in an operant test chamber resulted in food reinforcement according to a variable interval schedule of 15 sec. When saline was administered, the opposite lever was reinforced. A high degree of discriminated responding was observed when either 400 Μg/kg or 200 Μg/kg of nicotine was used as a discriminative stimulus. The degree of discrimination decreased as the length of the time period between the injection of nicotine and the test of discrimination was increased. This decline in discrimination was similar to the decline in brain levels of nicotine suggesting that nicotine discrimination is directly related to the concentration of nicotine in the brain. Atropine, mecamylamine, dibenamine, propranolol and α-methyl-para-tyrosine (AMPT) were all tested, in a range of doses, for effects upon nicotine discrimination. Of these, only mecamylamine antagonized the nicotine stimulus. These results indicate that the stimulus effect of nicotine is mediated specifically through nicotinic-cholinergic receptors and not muscarinic-cholinergic or adrenergic receptors.

Morphine and ?9-tetrahydrocannabinol: Tolerance to the stimulus effects

Morphine and saline served as discriminative Stimuli for one group of rats in a 2-lever discrimination task. δ 9-THC and vehicle were discriminative stimuli for a second group. Depression of one lever resulted in reinforcement following the administration of morphine or δ 9-THC and the opposite lever was reinforced after vehicle. A high degree of discriminated responding occurred with both drugs. During daily supplemental injections of morphine or δ 9-THC up to several times the training dose for a period of 2 months, subjects still discriminated morphine or δ 9-THC from vehicle. However, the degree of discrimination was reduced indicating a limited tolerance to either drug. Naloxone precipitated narcoticlike withdrawal symptoms in rats chronically treated with either morphine or δ 9-THC, indicating that there is an interaction between chronic administration of δ 9-THC and the narcotic antagonist, naloxone.