Construct validity of a self-stimulation threshold paradigm: effects of reward and performance manipulations.

A discrete-trial current-threshold intracranial self-stimulation (ICSS) paradigm has been used extensively to examine the effects of drugs on reward thresholds. However, there is little work to date validating that this specific procedure measures reward. The purpose of the present study was to establish the construct validity of this procedure by testing the procedure's ability to measure reward effects and to discriminate these reward effects from performance effects. The discrete-trial ICSS procedure provides four measures: current thresholds, response latency, extra responses and time-out responses. The effects of a performance manipulation (variations in the force required to operate the manipulandum) and of a reward manipulation (variations in the train duration of the electrical stimulation) were evaluated on the four measures. Reward effects were reflected primarily in changes in thresholds, with no effect on any of the other three measures. Conversely, performance effects were reflected primarily in changes in response latency, extra responses and time-out responses, with only a small effect on thresholds. Finally, the paradigm's potential as a useful tool in the elucidation of the neurobiological basis of reward was demonstrated by investigating the effects of two pharmacological agents, cocaine and curare, on the four measures derived from the discrete-trial current-threshold ICSS procedure. The results suggest that the discrete-trial current-threshold procedure can readily discriminate reward from performance treatments.     

The absolute refractory periods of self-stimulation neurons.

A new method is described for measuring the separate contributions of absolute refractory periods (ARPs), relative refractory periods (RRPs) and supernormal periods (SNPs) of the directly stimulated neurons mediating rewarding brain stimulation, to behaviorally measured excitability estimates. If pulse pairs are presented in which the first pulse in each pair is either higher, lower or equal in current to the second pulse in each pair, then ARPs, RRPs and SNPs contribute differentially. ARPs were found to make contributions at intrapair intervals between 0.4 and 1.2 msec, but were largest between 0.6 and 1.0 msec. RRPs made inappreciable contributions at all intrapair intervals. SNPs were found to make large contributions, particularly at intrapair intervals of 3.0 and 5.0 msec. Results for a dorsal pons placement were similar to those for two medial forebrain bundle placements.     

The changing immunological paradigm in coeliac disease

When coeliac disease is referred to as an inflammatory disorder, this may detract from its true nature. Activation of innate and adaptive immunity takes place in the mucosal lesion, but the tissue reaction is not that of classical inflammation. In fact, coeliac disease contrasts strikingly with typical inflammatory bowel disorders such as ulcerative colitis and Crohn's disease. The coeliac lesion apparently reflects, in the main, immune-driven remodelling of mucosal architecture with only a minor inflammatory component - initially most likely resulting from innate signals. Complement split products might be one of several potential initial hits that lead to activation of lamina propria and epithelial cells with release of mediators such as interleukin-15. This cytokine appears to stimulate potentially pathogenic intraepithelial lymphocytes. In genetically susceptible individuals, such early innate events could turn into persistent pathogenic signalling with subsequent adaptive cellular and humoral immunopathology resulting in a chronic lesion. Nevertheless, mucosal homeostasis is surprisingly well preserved as signified by the remarkable dominance of plasma cells that produce dimeric immunoglobulin A as a basis for enhanced secretory immunity. This shows that the microvascular endothelium in the lesion largely maintains its 'gatekeeper' function for mucosal immune cells - in striking contrast to the 'promiscuous' situation in inflammatory bowel disease. Altogether, a two-signal model is emerging for the pathogenesis of coeliac disease - signal 1 generated by innate immunity and signal 2 by adaptive immunity. Hence, there is currently an increased focus on immune activation in the epithelial compartment rather than on changes in the microvasculature as a basis for classical inflammation.     

Sleep induced by hypothalamic self-stimulation in cat

Effects of varying the voltage of the electrical stimulus used for self-stimulation of the mammillary region of the hypothalamus were studied. A behavioural sleep with EEG synchronization was induced by self-stimulation with medium voltages. Self-stimulation of the same locus either with threshold or with the optimum voltages (i.e. by which the highest lever-pressing rate was obtained) failed to induce such a peculiar effect.     

Reward saturation in medial forebrain bundle self-stimulation

A rate-frequency curve in self-stimulation experiments plots the response rate as a function of the frequency of stimulation pulses, yielding a steeply rising, roughly sigmoidal curve. Altering stimulation reward efficacy results in lateral shifts of this curve, while altering the operant performance capacity of the rat results in primarily vertical shifts. One hypothesis explaining the lateral stability of the curve in the face of performance-altering manipulations is that the stimulation reward effect saturates at the frequency where the curve asymptotes. In the first experiment we determined the frequency of rate-frequency curve asymptote in two paradigms, runway and lever-pressing, and compared it to the reward saturation frequency determined in a discrete choice procedure. Results indicate that reward often saturates at frequencies above the rate-frequency asymptote point, which does not support the above hypothesis; levelling-off of the rate-frequency function is most likely a result of performance ceiling factors. In a second experiment, increases in stimulation current reduced the saturation frequency, indicating that saturation is not determined by an upper limit on the signal carrying capacity of the directly excited axons.     

Lateral hypothalamic self-stimulation pathways in Rattus norvegicus

Self-stimulation in lateral hypothalamus involves the activation of several ascending and descending fiber systems. In an effort to define these fiber systems, self-stimulation loci were studied with a single low current level and bipolar nichrome electrodes made with wire 78.7 μ dia. Prograde degeneration revealed by the Fink-Heimer technique and retrograde chromatolytic changes were described following lesions at self-stimulation sites. Neuronal activity following electrical stimulation of self-stimulation sites was also used to define the functional influence of these fiber systems. The relationship with the extrapyramidal system was emphasized, with convergent evidence suggesting an intimate relation between lateral hypothalamic neurons and those of substantia nigra, pars compacta.     

Dissociating the determinants of self-stimulation

Four experiments were conducted to elucidate the determinants of the initiation of and escape from electrical stimulation of the lateral hypothalamus under several different reinforcement schedules. The first experiment of this series used correlational and factor analytic techniques to show that, under continuous reinforcement, the vigour of initiation is determined more by forcement than by positive reinforcement. Forcement is defined as all of the performance changes directly elicited and potentiated by the stimulation. Escape is determined by adaptation of positive reinforcement, not by negative reinforcement or aversion. Continuous reinforcement schedules are, therefore, not appropriate for studying either the positive or negative reinforcement produced by brain stimulation. The second experiment used fixed-interval reinforcement schedules to eliminate the effects of forcement on initiation and adaptation of positive reinforcement on escape. Parametric manipulations indicate that activity in the positive reinforcement and escape systems is a simple function of stimulation charge. The combination of parameters which make up a given charge is of relatively little importance. However, the positive reinforcement system becomes maximally activated at far lower charges than does the escape system. The third experiment used a T-maze technique to show that, after 5 sec, anterior hypothalamic stimulation becomes negatively reinforcing, but posterior hypothalamic stimulation does not. Since the escape from posterior hypothalamic stimulation on a fixed-interval schedule can be dissociated from both negative reinforcement and adaptation of positive reinforcement, it is suggested that such escape is reinforced by a positive process triggered by the offset of stimulation (OFF positive reinforcement). The fourth experiment showed that stimulation trains longer than 10 sec are significantly less positively reinforcing than much shorter trains. This reduction in positive reinforcement confirms the development of negative reinforcement in long trains of hypothalamic stimulation, even at posterior electrodes. Negative reinforcement appears to be as general a property of hypothalamic stimulation as is positive reinforcement. Thus, depending on the reinforcement schedule and electrode site, the initiation of lateral hypothalamic stimulation may be determined by ON positive reinforcement, OFF positive reinforcement and forcement. Escape may be determined by OFF positive reinforcement, adaptation of positive reinforcement and negative reinforcement.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effect of psychotropic drugs on self-stimulation

Amphetamine and cocaine have been shown to facilitate septal self-stimulation. Morphine, imipramine, benactyzine, meprobamate,diazepam, chlordiazepoxide, phenobarbital, and DLK-25, in small doses do not affect, but in large doses inhibit this reaction. It is suggested that amphetamine and cocaine have a direct activating effect on the positive reinforcement system of the septum. The ineffectiveness of the other drugs is explained by the absence of a nervous substrate for negative reinforcement at the septal level. Comparative analysis of the effect of psychotropic drugs on septal and hypothalamic self-stimulation leads to the conclusion that the activating effect of psychtropic drugs on the positive reinforcement system depends on their action on the emotiogenic structures of the brain and not on structures responsible for the formation of motivations.Laboratory for the Search and Study of Measures for the Prevention and Treatment of Drug Addiction, Department of Pharmacology, Institute of Pharmacology, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 83, No. 4, pp. 429–432, April, 1977.     

Parametric manipulations and fixed-interval self-stimulation.

Three experiments investigated hypothalamic self-stimulation under a fixed-interval (FI) reinforcement schedule. An FI 20-s schedule was chosen to reduce stimulation density in order to minimize the influence of priming effects or stimulation aftereffects that can affect responding under other schedules of reinforcement. The first experiment showed that the influence of train duration is greatest at levels up to 1 s and thereafter level off over a wide range of train durations (1-32 s). The second experiment showed that altering frequency, current, or pulse width produced almost identical changes in FI responding. These findings show that the neutral network subserving hypothalamic self-stimulation simply integrates the amount of charge over time. It is relatively insensitive to the combination of stimulation parameters that make up a given waveform. In the third experiment, the chronaxies from the strength-duration curves indicate the neural substrate supporting self-stimulation has a great current-integrating capacity. Together, these experiments show that varying the amount of brain stimulation produce large and consistent changes in a number of FI response measures. These measures effectively describe different attributes of FI performance and include response rate, the postreinforcement pause, interresponse times of short duration and the temporal distribution of responses within the interval.