Robert L. Hakan

Exposure to nicotine enhances the behavioral stimulant effect of nicotine and increases binding of [3H] acetylcholine to nicotinic receptors

Rats were given daily injections of nicotine sulfate in doses ranging from 0.1 to 0.4 mg/kg. The behavioral effect of these injections was measured as locomotor activity in photocell cages. Repeated administration of the same dose to each rat resulted in an enhancement of the stimulant effect of nicotine. This enhanced behavioral effect was quite pronounced within 5 days of repeated injection. Tissue from the cerebral cortex of these rats, exposed to nicotine for 5 days, was assayed for binding of [3H]acetylcholine to nicotinic receptors. These relatively small doses of nicotine resulted in 18-26% increases in cortical nicotinic receptors, compared to saline-treated rats. Rats exposed to 0.2 mg/kg of nicotine for 5 days and then given saline for 7 days still showed an enhanced behavioral response to nicotine on the eighth day after exposure, and nicotinic binding in the cortex was still elevated. However, 21 days after exposure to nicotine both the behavioral response to nicotine and the binding values had returned to the same values as those of saline-treated rats. These data imply that increased binding of [3H]acetylcholine to nicotinic sites and the enhanced behavioral effect of nicotine are functionally linked.

Chronic nicotine and locomotor activity: influences of exposure dose and test dose

Repeated exposure to nicotine increases both the number of central nicotinic receptors and the behavioral stimulant effect of nicotine. In the present experiments, the behavioral response to nicotine was examined in photocell activity cages. Groups of rats were tested using doses from 0.1 to 1.6 mg/kg both before and after all rats were exposed for 5 days to a common dose of 0.2 mg/kg/day. Prior to the 5-day exposure, there was a dose-related stimulant response to nicotine, with a maximum response seen at 0.4 mg/kg. After the 5-day exposure, the dose-effect curve was shifted upward, so that greater stimulation was produced at each test dose of nicotine.Other groups of rats were exposed for 5 days to doses of nicotine ranging from 0.01 to 0.30 mg/kg/day. On the 6th day all rats received a common test dose of 0.2 mg/kg and their response was measured in the activity cages. In animals exposed to 0.01 mg/kg/day, the test day response was not different from saline controls, but the groups exposed to higher doses showed increased stimulation in response to the common test dose. Measurements of nicotinic receptor binding using [3H]-acetylcholine found increased binding in groups receiving 0.03 mg/kg/day or more, but not in the group that received 0.01 mg/kg/day.The correspondence between the doses that increase behavioral stimulant reactions to nicotine and the doses that increase nicotinic binding suggest that increased receptor numbers may be responsible for the increased behavioral stimulation. However, rats given high doses (1.6 mg/kg, twice per day) did not show increased behavioral stimulation to a test dose of 0.2 mg/kg. In those rats, receptor binding was increased even more than in rats exposed to lower chronic doses. Several hypotheses are offered for this apparent discrepancy.

DISTRIBUTION OF AMYGDALA INPUT TO THE NUCLEUS ACCUMBENS SEPTI : AN ELECTROPHYSIOLOGICAL INVESTIGATION

The nucleus accumbens septi (NAS) receives afferent input from the amygdala via the stria terminalis and from the hippocampus via the fimbria. Extracellular recordings from 196 NAS neurons in halothane-anesthetized rats revealed heterogeneous response patterns following stimulation of the amygdala. The observation that 30% of anterior NAS units but only 16% of posterior NAS units were responsive to amygdala stimulation suggested a topographical arrangement of amygdala efferents. Comparing the effects of amygdala and fimbria stimulation revealed that the two afferent pathways converge onto individual NAS neurons, but that the two sites of stimulation can differentially influence other neurons. The present results clarify the topographical distribution of amygdala input to the NAS, confirm that inputs from two limbic structures are integrated within the NAS, and further illustrate the electrophysiological heterogeneity of NAS neurons.

Electrophysiological evidence for reciprocal connectivity between the nucleus accumbens septi and ventral pallidal region

Responses of nucleus accumbens (NAS) neurons to ventral pallidum (VP) stimulation were examined in anesthetized rats. Results demonstrated: (1) NAS to VP projection neurons reside primarily in the relatively lateral aspects of the NAS, and (2) substantial VP to NAS feedback also exists. These feedback projections are widely distributed throughout the NAS. Moreover, functionally identifiable NAS neuronal subpopulations were revealed by analysis of unit responses to concurrent VP and fimbria stimulation: (1) most, but not all NAS units responded to VP and fimbria stimulation in qualitatively divergent ways; (2) many NAS units demonstrated monosynaptic convergence of fimbria and VP terminations onto individual NAS units; and (3) in other cases, identified NAS-VP projection neurons were also monosynaptically activated by fimbria stimulation.

Nicotine induced locomotor activity in rats: The role of Pavlovian conditioning

Rats repeatedly exposed to small doses of nicotine will demonstrate a significant augmentation of locomotor activity in response to a subsequent test dose of nicotine. A sensitization of brain tissue is hypothesized to account for this effect but Pavlovian conditioning might also be a major factor. Therefore the present study assessed the possible role of Pavlovian conditioning in this nicotine effect. Two experiments were conducted. In the first, subjects were administered either saline or nicotine in either their home cages or in activity test cages for five days. All subjects were then tested in the activity test cages on day six. In the second experiment rats were administered either nicotine or saline in the presence of a complex stimulus and later tested for response to nicotine alone and the complex stimulus alone. Results from these experiments indicate that Pavlovian conditioning does not play a major role in nicotines effect on locomotor activity.

Acute tolerance to the locomotor stimulant effects of nicotine in the rat

Studies of peripheral nicotinic receptors have revealed that, after an initial agonist action, the receptors remain inhibited either through continued depolarization blockade due to continued presence of the agonist or through a brief inactivation of the receptor following its activation. If a similar phenomenon occurs at central nervous system nicotinic receptors, then behavioral responses to nicotine should exhibit an acute tolerance (tachyphylaxis). Groups of rats were given either saline or 0.2 mg/kg nicotine injections at 20-min intervals in photocell activity cages. A progressive decline in the locomotor responsiveness to nicotine was observed. The time course of this acute tolerance was observed in other rats given initial 0.2 mg/kg nicotine injections followed at differing time intervals by second 0.2 mg/kg nicotine test injections. The secondary antagonism to nicotines locomotor stimulant effects was maximal at 45–60 min and recovered by 90–120 min. The locomotor response to 0.2 mg/kg nicotine test injections was observed in other rats following exposure to 1.8 mg/kg nicotine, and the behavioral response was attenuated for more than 5 h.

Electrophysiological analysis of the neural circuitry underlying opiate effects in the nucleus accumbens septi.

Systemically administered opiates inhibit or excite spontaneously active single units of the nucleus accumbens septi (NAS) but do not affect fimbria-evoked NAS responses. However, microinjections of morphine to the dopamine cell bodies of the ventral tegmental area (VTA-M) do inhibit these evoked responses. Since systemic heroin can reverse the inhibitory effect of VTA-M on the fimbria-evoked NAS responses, systemic opiates might exert actions on other brain regions that oppose the inhibitory effect of VTA-M on the NAS. Evidence is provided indicating that this opposing action can arise from opiate actions at the ventral subiculum of the hippocampus.

Aikido experience and its relation to mindfulness: A two-part study

The martial art Aikido may be useful in the development of mindfulness. In this study, the authors examined the potential association of training in Aikido may have on mindfulness. The sample of Study 1 comprised 159 participants completing two empirically validated scales of mindfulness and awareness, the Kentucky Inventory of Mindfulness Skills and the Mindfulness Attention Awareness Scale. Study 2 was a longitudinal study of 20 Aikido students from beginning through 5th Kyu (approximately 9 months of training). The results from both studies show significant increases in mindfulness scores with increased Aikido training.

Social Judgments as a Measure of Right Mindfulness

Mindfulness should be associated with decreased automatic responding and with increased empathy and compassion. Therefore, given an opportunity to express judgments about other people, a highly mindful person should be less inclined to express negative and unnecessary judgments. The present study provided participants the opportunity to express judgments about photographs of other people in a procedure that attempted to control for potential demand characteristics associated with self-report measures of mindfulness. Expressed judgments were panel rated, and the derived judgment scores were regressed with participant scores on the Mindful Attention Awareness Scale (MAAS) and the Five Facets of Mindfulness Questionnaire (FFMQ). Results demonstrated no overall significant relationship between judgments and MAAS or FFMQ total scores. However, a significant relationship between judgment scores and the “act with awareness” and the “non-judgment” facets of the FFMQ was observed. Judgment scores were also related to self-reported involvement in mindfulness activities such as meditation and yoga. These results suggest that self-reported mindfulness may not completely align with behaviors that logically reflect right mindfulness. Moreover, social judgment may be a useful overt measure related to mindfulness. The results also provide empirical evidence of the very strong social tendency to negatively and often derogatorily judge other people.

Dose-Related Nicotine Effects on CNS Binding and Behavior

Repeated nicotine exposures increase both central nicotinic receptor numbers and the behavioral stimulant effect of nicotine. In the present experiments, the behavioral effects of graded doses of nicotine (0.1 to 1.6 mg/kg, s.c.) were observed in photocell activity cages both before and after the rats were given five daily injections of 0.2 mg/kg nicotine in their home cages. Comparing the behavioral response after five days of exposure to the response prior to exposure revealed an upward shift in the dose-response curve (Fig. 1).