Robert D. Fitzgerald

Baroreceptor involvement in classically conditioned heart rate responses of restrained rats

A group (N = 8) of restrained, baroreceptor denervated rats and a sham-operated-control group (n = 8) received discriminated classical conditioning consisting of 30 reinforced trials in which a CS+ was paired with an electric shock US and 30 non-reinforced trials in which a different CS (CS-) was presented alone. The control group displayed a decelerative heart rate CR and a biphasic pressor-depressor blood pressure CR. The denervated group failed to show a heart rate CR but did show a pressor-only blood pressure CR. The URs of the denervated group consisted of a major depressor change in blood pressure and a slight tachycardia whereas the URs of the control group consisted of a slight pressor response and tachycardia. The results indicated that centrally initiated activity in the efferent vagal pathways mediating the decelerative HR CR in rats may be blocked by the absence of normal afferent baroreceptor neural discharge. An integrating role of baroreceptor input was also suggested for the URs.

Bidirectional heart rate responses in rats associated with excitatory and inhibitory stimuli

Following classical conditioning to a shock-reinforced tone CS (T1+), heart rate (HR) of three groups of rats was examined in response to a new reinforced tone (T2+) and a nonreinforced light (L−) CS given during conditioned inhibition (T2+ vs. T1L−), discrimination conditioning (T2+ vs. L−), or explicitly unpaired (T2/L− vs. US alone) procedures. Decelerative HR reactions occurred to the reinforced T2+ and T2+ CSs. To the respective nonreinforced CSs, the conditioned inhibition group displayed diminished but sizable HR deceleration, the discrimination group showed near-zero responding, and the explicitly upaired group showed HR acceleration. Subsequent reversal conditioning to L was retarded in the conditioned inhibition and explicitly unpaired groups relative to the discrimination group. Group differences on combined-cue [T2/L−) trials were not found. Both the HR responses during inhibitory training and the reversal-conditioning impairments suggest that inhibition may have been established to L− in the conditioned inhibition and explicitly unpaired groups.

Impaired learning of classically conditioned bradycardia in rats following fourth ventricle administration of D-Ala2-methionine-enkephalinamide.

Prior to differential classical conditioning on two successive days, three groups of rats received an infusion (10 micrograms) of either the opioid peptide D-alanine2-methionine-enkephalinamide (DALA), DALA plus naltrexone (5 micrograms), or saline into the rostral region of the fourth ventricle. A fourth group, which served as a control to help localize DALAs site of action, received an infusion of DALA (10 micrograms) into the brain stem area on the floor of the ventricle. The group given DALA alone in the ventricle showed no evidence of a heart rate conditioned response (CR) either during conditioning or during a nondrug test session given 2 days after conditioning. Interference with the CR by DALA was reversed by the concomitant infusion of naltrexone. The control group given DALA in the brain stem developed a normal CR. It was suggested that DALA-induced opioid-receptor activity in the region of the periaqueductal/periventricular gray or locus coeruleus region of the ventricle may have prevented the learning of a CR. This could have occurred through a blunting of the emotional aftereffects of the unconditioned stimulus or through interference with projection pathways to other areas.

Classically conditioned heart rate and respiratory-motor activity in newborn and neonatal pygmy goats

Classical discrimination conditioning of heart rate (HR) and respiratory-motor (RM) activity was examined in 16 newborn (average age = 1 day) and 8 neonatal (average age = 2 weeks) pygmy goats over 4 days of conditioning involving an electric shock US and auditory CSs. On the 4th day, one-half of the animals in each group received a low to moderate dose of ethanol to test the resistance of the CRs to drug effects. Discriminated conditioning of RM activity but not HR occurred in the newborn group, indicating an absence of close coupling between skeletal-motor activity and HR at this early age. While the newborn group failed to show recognizable HR reactions to the CSs during the 4 days of testing, it did show a long-latency brady-cardia UR beginning at 2 days of age that may have been secondary to baroreceptor reflex actions. The neonatal group displayed conditioning of both HR and RM activity. The similar latencies of the two types of CRs during the CS suggested that they may have been related to each other. However, the fact that the RM CR developed a day before the HR CR, combined with the observation that ethanol modified the HR CR but not the RM CR, supports the view that there was considerable independence between the two types of CRs.

Classically conditioned bradycardia and skeletal-motor activity in restrained rats

Classical conditioning of heart rate (HR) and skeletal-motor activity in restrained rats was examined using a single, brief (.5-msec) pulse of shock to the rat’s tail as both the CS and US. Electric shock was selected as a CS to discourage behavioral freezing and to provide an above-zero level of movement activity for evaluating the presence of conditioning. Three CS intensities and two US intensities were combined in a factorial design creating six separate experimental groups which received 50 paired trace conditioning trials at a CS-US interval of 8.1 sec. Three control groups were given 50 unpaired presentations of one of the CSs and the highest intensity US. All of the experimental groups showed the development of a bradycardia CR in the absence of a conditioned change in movement. During conditioning, HR and movement to CS onset varied together in both the experimental and control groups. Other examples of a close correspondence between HR and movement included some, but not all, of the preconditioning CS-alone responses, the URs, and shifts in baselines. The results suggested that although some nonassociatively based HR changes may have been tied to movement, the conditioned bradycardias in the experimental groups appeared to be relatively independent of movement.

Effects of centrally administered anxiolytic agents on classically conditioned bradycardia.

Rats received infusions of the opioid peptide D-Ala2-Met-enkephalinamide (DALA, 10 micrograms), the alpha 2-noradrenergic agonist clonidine (CLON, 3 micrograms), UK14,304 (UK, 5 micrograms), the corticotropin-releasing factor (CRF) antagonist alpha-helical CRF (9-41) (alpha-HEL, 25 micrograms), or saline in the rostral fourth ventricle. The DALA, CLON, and UK groups showed no evidence of a heart rate (HR) conditioned response (CR) during conditioning, after antagonist administration, or on a nondrug test 48 hr after conditioning. These three groups showed the development of normal CRs when later retrained without drugs. The alpha-HEL group showed an enhanced CR. During a subsequent startle test, the presence of a conditioned stimulus resulted in a pronounced suppression of startle in the SAL and alpha-HEL groups but had no effects on startle in the DALA, CLON, and UK groups. The results indicate an important role for fourth ventricle structures containing opioid and alpha 2 receptors in the learning of an HR CR.

Opposing heart rate reactions associated with behavioral states of excitation and inhibition.

Following the development of an excitatory bradycardia conditioned response (CR) to a CS+ paired with a shock US on Day 1, three groups of rats were given one of three inhibitory training procedures on Day 2 with a different CS (CS-). Then on Day 3 the inhibitory capacity of each CS- was examined on a modified combined cue test in which CS- was given slightly before CS+ and on a reversal conditioning test in which CS- was now paired with the US. The three inhibitory procedures consisted of CS- alone (CSA) trials, explicitly unpaired (EUP) CS- and US trials, and truly random (TR) CS- and US trials. During inhibitory training, the bradycardia CR to CS+ was replaced with a tachycardia reaction to CS- in the EUP group but not in the other groups. Subsequent to inhibitory training the EUP group and to some extent also the TR group showed a decrement in the excitatory bradycardia response to CS+ when compared to the robust HR slowdowns displayed by the CSA group. It was suggested, within the context of opponent process theory, that the separate USs given the EUP and TR groups (especially the former) during inhibitory training may have led to conditioning of inhibitory tendencies to CS- and that these in turn generalized and decremented previous established bradycardia responding to CS+ and the development of a new bradycardia to CS- during reversal conditioning.

Morphine influences on classical aversive conditioned heart rate in rats.

The present series of three experiments was concerned with the effects of morphine and the morphine antagonist naloxone on the development of a classical aversive heart rate (HR) conditioned response (CR) to a tone conditioned stimulus (CS) paired with an electric shock unconditioned stimulus (US). In the first study, separate groups of rats received preconditioning sc injections of either 0.25 mg/kg, 5 mg/kg, or 10 mg/kg of morphine. Three other groups were given 0.1 mg/kg, 5 mg/kg, or 10 mg/kg of naloxone alone. All of the morphine groups showed attenuation HR responses to the CS on preconditioning CS-alone trials. During conditioning, the 10-mg/kg morphine group showed a markedly decremented bradycardia CR and tachycardia unconditioned response (UR), whereas the 5-mg/kg morphine group showed a normal CR in combination with a decremented UR. Naloxone had no measurable effects on HR. In the second study, naloxone (1 mg/kg) given after conditioning failed to reverse the CR and UR losses produced by 10 mg/kg of morphine given prior to conditioning. Administration of 10 mg/kg of morphine produced only a minor reduction in a HR CR established in a drug-free state, but the tachycardia UR was severely reduced. The results of the third study showed that 1 mg/kg of naloxone was effective in reversing analgesia induced by 10 mg/kg of morphine, as indexed by the tail-flick test. Taken together, the results suggest that the 10-mg/kg dose of morphine interfered with the learning of a HR CR, perhaps principally by reducing the aversive or emotional consequences of the shock US. Direct cardiovascular effects of morphine seemed to interfere with the performance of the tachycardia UR, but not with the performance of the bradycardia CR.

Learning versus performance effects of cocaine on discriminative heart rate conditioning in rats

The study examined the effects of cocaine on learning and performance of a classically conditioned heart rate (HR) discrimination in rats involving two auditory conditioned stimuli (CSs). In the discrimination protocol, one CS (CS+) was paired with the shock unconditioned stimulus (US) on a consistent basis and the other CS (CS−) was always presented alone. Four groups received an IP injection of 1, 3, 10, or 30 mg/kg cocaine and a fifth group received saline. Shortly after the injections, all groups were given six CS-alone trials, followed by 24 randomly sequenced discrimination conditioning trials (12 CS+ and 12 CS−). Approximately 72 h later, all groups were given six test trials with each CS in the absence of cocaine to evaluate the presence or absence of discrimination learning. All cocaine groups showed impaired discrimination performance on the discrimination conditioning trials, reductions in early pretest CS-alone responses, and reductions in resting HR. However, on the non-drug test trials discrimination performance was normal in all cocaine groups. The results established that in spite of major changes in HR dynamics, learning of the HR discrimination was not affected by cocaine but that cocaine did interfere with the performance of the discrimination. Except for the highest 30 mg group, the performance decrement appeared to be related to a cocaine-produced reduction in the capacity to inhibit bradycardia responding to the safe CS−. It was suggested that this loss of inhibitory control may have been due to cocaine changes in a corticothalamic pathway that controls inhibition of bradycardia to a safe CS−.