Effects of standardized extracts of St. John's wort on the single-unit activity of serotonergic dorsal Raphe neurons in awake cats: comparisons with fluoxetine and sertraline.

St. John's wort is widely used as an herbal remedy for depression. Although its mechanism of action remains unknown, some evidence suggests that St. John's wort might act via brain serotonin (e.g., as a serotonin reuptake inhibitor). To determine whether St. John's wort affects the central serotonergic system, we monitored the discharge rate of serotonin-containing neurons in the dorsal raphe nucleus of awake cats following systemic administration of two clinical preparations of St. John's wort, Jarsin 300 (15-600 mg/kg, p.o.) and Hyperforat (0.5-4.0 ml, i.v.). Both preparations were found to have no effect on neuronal activity. This contrasts sharply with the action of fluoxetine and sertraline (2 mg/kg, p.o.), two selective serotonin reuptake inhibitors (SSRIs), which markedly depressed neuronal activity by increasing the synaptic availability of serotonin at inhibitory somatodendritic 5-HT(1A) autoreceptors. The failure of St. John's wort to depress neuronal activity cannot be attributed to an impairment of the 5-HT(1A) autoreceptor mechanism, since pretreatment with Jarsin 300 (300 mg/kg, p.o.) did not alter the responsiveness of serotonergic neurons to the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (10 microg/kg, i.v.). Overall, these findings indicate that the mode of action of St. John's wort is different from that of conventional antidepressant drugs, which elevate brain serotonin and evoke negative feedback control of serotonergic neurons.

Single-unit responses of serotonergic dorsal raphe neurons to specific motor challenges in freely moving cats.

Serotonin has been hypothesized to play an important role in the central control of motor function. Consistent with this hypothesis, virtually all serotonergic neurons within the medullary nuclei raphe obscurus and raphe pallidus in cats are activated in response to specific motor challenges. To determine whether the response profile of serotonergic neurons in the midbrain is similar to that observed in the medulla, the single-unit activity of serotonergic dorsal raphe nucleus cells was studied during three specific motor activities: treadmill-induced locomotion, hypercarbia-induced ventilatory response and spontaneous feeding. In contrast to the results obtained for medullary raphe cells, none of the serotonergic dorsal raphe cells studied (n=26) demonstrated increased firing during treadmill-induced locomotion. A subset of serotonergic dorsal raphe cells (8/36) responded to the hypercarbic ventilatory challenge with increased firing rates that were directly related to the fraction of inspired carbon dioxide, and a non-overlapping subset of cells (6/31) was activated during feeding. All feeding-on cells demonstrated a rapid activation and de-activation coincident with feeding onset and offset, respectively. Although the proportions of serotonergic cells activated by hypercarbia or feeding in the dorsal raphe nucleus were similar to those found in the medullary raphe, there were several major distinctions in the response characteristics for the two cell groups. In contrast to the medullary serotonergic neurons, only a minority of dorsal raphe nucleus serotonergic neurons responded to a motor challenge. Overall, the above results suggest very different roles for the midbrain and medullary serotonergic neurons in response to motor activities.

Single-unit responses of serotonergic medullary and pontine raphe neurons to environmental cooling in freely moving cats.

Brain serotonin has long been implicated in the regulation of body temperature, although its precise role is not completely understood. The present study examined the effects of environmental cooling (4-8 degrees C for 2 or 4h) on the single-unit activity of serotonergic neurons recorded in the medullary raphe nuclei obscurus and pallidus and in the pontine dorsal raphe nucleus of freely moving cats. These neuronal groups have primarily descending projections to the spinal cord and ascending projections to the forebrain, respectively. Cold exposure induced shivering and piloerection, but no appreciable changes in core temperature. Of the medullary serotonergic cells studied (n=14), seven were activated and seven were unresponsive to cold exposure. For the responsive cells, the mean increase and peak effect in unit activity relative to baseline were 31% and 46%, respectively. Of the seven cold-responsive cells, the activity of four was monitored when the animals were transferred back to room temperature (23 degrees C). Within 15-30 min, the activity of these cells returned to baseline. In contrast, none of the dorsal raphe nucleus cells studied (n=14) displayed a significant change in neuronal activity during cold exposure, suggesting that these neurons do not receive afferent input from cold-sensitive cutaneous receptors or participate in thermoregulatory responses evoked by low ambient temperatures.Overall, these results suggest that a subset of medullary serotonergic neurons play a role in physiological mechanisms underlying cold defense (e.g. increases in motor output and/or autonomic outflow). On the other hand, the lack of responsiveness of serotonergic dorsal raphe nucleus neurons to cold exposure does not support a specific role for these cells in thermoregulation.

Alcohol aversion generalization in rats: specific disruption of taste and odor cues with gustatory neocortex or olfactory bulb ablations.

Rats with ablations of the gustatory neocortex (Experiment 1) and rats with olfactory bulb ablations (Experiment 2) were compared with normal rats for aversion generalization to both single taste solutions (sucrose, sodium chloride, quinine hydrochloride, hydrochloric acid) and compound taste solutions (pairs of the four single tastants) following alcohol aversion training. All rats acquired equal and strong alcohol aversions. Control rats showed consistent aversion generalization to both the sucrose + quinine and the sucrose + hydrochloric acid solutions; no significant generalization occurred to the single tastants except a weak generalization to sucrose in Experiment 2. Rats with gustatory neocortical ablations failed to show aversion generalization to any of the taste solutions. Rats with olfactory bulbectomies displayed the same aversion generalization functions as control rats but exhibited significantly faster extinction of the alcohol aversion than did the trained control rats. Results from the present experiments suggest that during alcohol aversion learning, rats lacking gustatory neocortex use odor cues (no taste generalization), whereas rats lacking olfactory bulbs utilize taste cues (normal taste generalization).

Facilitation of masseter EMG and masseteric (jaw-closure) reflex by serotonin in behaving cats.

The trigeminal motor nucleus (MoV) contains the somata of the motoneurons that control jaw position and jaw movements. This nucleus is of neurochemical interest because it receives a dense serotonergic input. We examined the effects of application of serotonin or fluoxetine, a serotonin reuptake blocker, into this nucleus on the spontaneous or reflex (jaw-closure) electrical activity of the masseter muscle in behaving cats. Serotonin produced a clearcut enhancement of both spontaneous and reflex activities. This action was attenuated by previous systemic injection of the serotonin receptor antagonist methysergide. The effect was mimicked to a certain extent by fluoxetine. These data provide evidence that the serotonergic input to MoV exerts a general facilitatory influence on masseter motoneurons activity.

5-HT1A agonists induce hippocampal theta activity in freely moving cats: role of presynaptic 5-HT1A receptors.

Electrical activity in the dorsal hippocampus was recorded in freely moving cats in response to intravenous administration of 5-HT1A agonist and antagonist drugs. Administration of low doses of the selective 5-HT1A agonists 8-OH-DPAT (5-20 micrograms/kg) and ipsapirone (20-100 micrograms/kg) produced rhythmic slow activity (theta) in the hippocampal EEG within 30 s. Similar effects were observed with BMY 7378 (20 and 100 micrograms/kg), which acts as an agonist at presynaptic (somatodendritic) 5-HT1A receptors and as an antagonist at postsynaptic 5-HT1A receptors. Power spectral analyses showed that all three compounds produced a dose-dependent increase in the EEG power occurring in the theta frequency band (3.5-8.0 Hz) as a proportion of total power from 0.25 to 30.0 Hz (relative theta power). The increase in relative theta power produced by 8-OH-DPAT (20 micrograms/kg) was greatly attenuated by spiperone (1 mg/kg), a highly effective 5-HT1A autoreceptor antagonist. Administration of spiperone alone had no significant effect on relative theta power. These results are discussed in relationship to the effects of these drugs on serotonergic neuronal activity. Our results suggest that preferential activation of presynaptic 5-HT1A receptors, and subsequent inhibition of serotonin neurotransmission, facilitates the appearance of hippocampal theta activity in awake cats.

A subgroup of dorsal raphe serotonergic neurons in the cat is strongly activated during oral-buccal movements.

A subgroup of approximately 25% of dorsal raphe nucleus serotonergic neurons in cat was strongly activated in association with oral-buccal movements, such as chewing, licking, and grooming. The mean magnitude of increase in neuronal activity for these cells was approximately 100% above the spontaneous waking level. However, some of these cells were activated by as much as 200-300%. The neuronal activation frequently preceded the initiation of the movement and stopped abruptly in association with either pauses in the motor sequence or with its cessation. Most of the neurons in this subgroup were also strongly and preferentially activated by somatosensory stimuli applied to the head, neck, and face. During orientation to a strong or novel stimulus, the activity of these neurons fell silent for periods of 1-5 s. These data and results from our previous studies of medullary raphe neurons are discussed within the context of the general role of serotonin in tonic and central pattern generator-related motor activity.

Venlafaxine and its interaction with WAY 100635: effects on serotonergic unit activity and behavior in cats.

The therapeutic efficacy of antidepressant drugs that inhibit the reuptake of serotonin (5-hydroxytryptamine, 5-HT) may be enhanced by blocking their indirect activation of 5-HT(1A) autoreceptors, which mediate feedback inhibition of serotonergic neuronal activity. In this study, we examined the effects of venlafaxine, a dual 5-HT/noradrenaline reuptake inhibitor, alone and in combination with the selective 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexanecarboxamide (WAY 100635), on the single-unit activity of serotonergic dorsal raphe neurons and concurrent behavior in freely moving cats. Systemic administration of venlafaxine (0.05-1.0 mg/kg, i.v.) produced a dose-dependent decrease in firing rate (ED(50)=0.19 mg/kg), with virtually complete inhibition of neuronal discharge at the highest dose tested. The subsequent administration of WAY 100635 (0.1 mg/kg, i.v.) rapidly reversed the neuronal suppression produced by venlafaxine and significantly elevated the firing rate above baseline levels. The overshoot in neuronal activity was associated with the onset of an adverse behavioral reaction resembling the 5-HT syndrome resulting from excessive levels of brain 5-HT. The intensity of this reaction paralleled the degree of neuronal restoration induced by WAY 100635, suggesting a causal relationship. Such behavioral responses were either not observed previously, or of a low intensity, when WAY 100635 was combined with selective 5-HT reuptake inhibitors. Overall, these results suggest that the risk of inducing adverse effects, such as the 5-HT syndrome, may be higher with dual 5-HT/noradrenaline reuptake inhibitors than with selective 5-HT reuptake inhibitors, when these agents are combined with a potent 5-HT(1A) autoreceptor antagonist. Possible mechanisms that might account for these differences in drug interaction are discussed.

The 5-HT1A receptor antagonist p-MPPI blocks 5-HT1A autoreceptors and increases dorsal raphe unit activity in awake cats.

The effects of the putative 5-HT1A receptor antagonist 4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinyl-benzam ide (p-MPPI) were examined on the activity of serotonergic dorsal raphe nucleus neurons in freely moving cats. Systemic administration of p-MPPI produced a dose-dependent increase in firing rate. This stimulatory effect of p-MPPI was evident during wakefulness (when serotonergic neurons display a relatively high level of activity), but not during sleep (when serotonergic neurons display little or no spontaneous activity). p-MPPI also blocked the ability of the 5-HT1A receptor agonist 8-hydroxy-(2-di-n-propylamino)tetralin (8-OH-DPAT) to inhibit serotonergic neuronal activity. This antagonism was evident both as a reversal of the neuronal inhibition produced by prior injection of 8-OH-DPAT and as a shift in the potency of 8-OH-DPAT following p-MPPI pretreatment. Overall, these results in behaving animals indicate that p-MPPI acts as an effective 5-HT1A autoreceptor antagonist. The increase in firing rate produced by p-MPPI supports the hypothesis that autoreceptor-mediated feedback inhibition operates under physiological conditions.

Pindolol increases extracellular 5-HT while inhibiting serotonergic neuronal activity.

The effects of pindolol, a beta-adrenoceptor blocker/putative 5-hydroxytryptamine (5-HT)1A/1B antagonist, on both the single-unit activity of serotonergic neurons in the dorsal raphe nucleus (DRN) and extracellular 5-HT levels in the caudate nucleus, were examined in freely moving cats. Administration of (+)-pindolol (1 and 10 mg/kg, s.c.) decreased neuronal activity and increased 5-HT levels in a dose- and time-dependent manner. The subsequent administration of WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl)cycloh exanecarboxamide] (0.2 mg/kg, s.c.), a selective 5-HT1A receptor antagonist, blocked pindolol-induced neuronal suppression and potentiated 5-HT output. These results indicate that pindolol may be acting at the level of the nerve terminal to increase 5-HT.

The effectiveness of a parenting skills program for parents of middle school students in small communities.

This study provides evidence of the effectiveness of behaviorally based parenting skills classes provided by carefully trained and supervised group leaders who were not mental health clinicians. A program for parents of at-risk middle school students was evaluated in a randomized controlled trial in 8 small Oregon communities. Parents (N = 303) were randomly assigned to immediate treatment or a wait-list condition. Data were analyzed using latent growth modeling. Participation in the program led to significant improvements in problem-solving interactions as indicated by parent reports and a Taped Situations Test. Parents' over-reactivity and laxness toward their children's behavior were reduced and their feelings toward their children improved significantly as a function of treatment. Parent-reported child antisocial behavior was also reduced.

Neocortical involvement in the acquisition and retention of learned alcohol aversions in rats.

In one experiment, rats lacking gustatory neocortex (GN) were compared with control (both normal and control lesion) rats in the acquisition of a learned alcohol aversion. In a second experiment, the effect of GN ablations on preoperatively learned alcohol aversions was examined. Results showed that rats lacking GN both learned and retained alcohol aversions in a normal manner. These same GN rats, however, extinguished the alcohol aversions significantly faster than controls. These results are in contrast to previous data which indicated that the integrity of the GN was necessary for normal acquisition and retention of learned taste aversions. It is suggested that the odor qualities present in the alcohol stimulus account for the relatively normal performance of GN rats.

Gustatory and olfactory contributions to alcohol consumption in rats.

To determine the relative contributions of taste and smell in the consumption of alcohol by rats, the present experiment tested normal rats (n = 14) and rats with either gustatory cortex ablations (n = 10), olfactory bulbectomies (n = 11), or combination gustatory cortex and olfactory bulb ablations (n = 12). Rats were tested under mild fluid deprivation using a two-bottle testing procedure. Thirteen concentrations of alcohol (0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, and 12%, v/v) were tested in ascending order. Results showed that at strong alcohol concentrations (7% through 11%) rats with combined gustatory cortex and olfactory bulb ablations consumed significantly more alcohol than normal control rats. Rats lacking gustatory cortex displayed a similar increased level of consumption with strong alcohol concentrations. It is suggested that the high level of consumption of strong alcohol concentrations by rats with central nervous system damage reflects an associative deficit rather than an alteration in taste or odor perception.

Learned alcohol aversions in rats: gustatory and olfactory components.

The gustatory and olfactory basis of learned alcohol aversions was examined by testing rats with either gustatory neocortex ablations, olfactory bulb ablations, or a combination of both ablations. In the first experiment operated rats were compared with control rats in the acquisition of a learned alcohol aversion. In the second experiment, the effect of ablations on preoperatively-learned alcohol aversions was examined. Rats lacking gustatory neocortex learned and retained alcohol aversions normally although these rats extinguished the aversions faster than normal rats. Olfactory bulb ablation alone failed to disrupt normal aversion learning but completely eliminated retention of a previously acquired aversion. Combination ablations produced severe deficits both in acquisition and retention of learned alcohol aversions. The results indicate that, besides having gustatory qualities, the odor quality of alcohol is important in determining the associative and memorial characteristics of alcohol.

Alcohol preference in rats lacking gustatory neocortex.

Ingestion of alcohol solutions (in concentrations from 0.5 to 12% v/v) was examined in three experiments where rats lacking gustatory neocortex (GN) were compared with intact and control lesion rats. Two experiments tested alcohol consumption during a restricted schedule of fluid access with one or two bottle tests. The last experiment involved testing with continuous access to water and alcohol solutions in two bottle tests. Subgroups of rats in each experiment were presented with either an ascending or descending order of concentrations. In all experiments, GN rats consumed less total fluid during testing (relative to control rats). In general, GN rats exhibited similar patterns of alcohol consumption as that found in control rats. Where differences between GN rats and control rats were found, GN rats consumed more alcohol than control rats during tests with restricted fluid access. During continuous fluid access, however, no significant differences between GN rats and control rats were found.

Development of adolescent problem behavior.

The developmental model of adolescent antisocial behavior advanced by Patterson and colleagues (e.g., Patterson, Reid, & Dishion, 1992) appears to generalize the development of a diverse set of problem behaviors. Structural equation modeling methods were applied to 18-month longitudinal data from 523 adolescents. The problem behavior construct included substance use, antisocial behavior, academic failure, and risky sexual behavior. Families with high levels of conflict were less likely to have high levels of parent-child involvement. Such family conditions resulted in less adequate parental monitoring of adolescent behavior, making associations with deviant peers more likely. Poor parental monitoring and associations with deviant peers were strong predictors of engagement in problem behavior. These constructs accounted for 46% of the variance in problem behavior. Although association with deviant peers was the most proximal social influence on problem behavior, parental monitoring and family factors (conflict and involvement) were key parenting practices that influenced this developmental process.

Increasing the prevalence of successful children: The case for community intervention research.

This paper makes a case for research on community interventions on child rearing. Sufficient evidence has accumulated about the development of children's problem behavior to justify evaluating efforts to reduce the prevalence of these problems in whole communities. The contextual risk factors for diverse child behavior problems are well understood, and interventions to ameliorate individual risk factors have been developed and evaluated. Because interventions with individual children have proven to be efficacious, it is now appropriate to direct energy toward reducing the prevalence of children with behavior problems. At the same time, existing interventions have limitations. Community interventions may be needed to modify the larger social context for families. This paper enumerates possible components of a community intervention to improve child-rearing outcomes. Existing evidence indicates that communities would benefit from making parent training and family support programs available to parents. Validated methods of identifying and remediating academic and behavioral problems in schools are available, but influencing schools to adopt them remains a problem. Community organizing could mobilize communities to allocate the resources necessary to support such parenting and schooling programs as well as encourage their adoption. Media campaigns could foster community support and directly influence parenting practices. Efforts to modify peer influences to use illicit substances have received empirical support; similar efforts may be relevant to preventing other problems. The development of a science of community interventions on child rearing is hampered by overreliance on randomized control trials. For this reason, two examples of time-series experimental evaluations of community intervention components are described here.

Response of serotonergic caudal raphe neurons in relation to specific motor activities in freely moving cats.

Serotonergic neuronal responses during three specific motor activities were studied in nuclei raphe obscurus (NRO) and raphe pallidus (NRP) of freely moving cats by means of extracellular single-unit recordings. Responses to treadmill-induced locomotion were primarily excitatory, with 21 of 24 neurons displaying increased firing rates, directly related to treadmill speed. Individual regression analyses determined three response patterns: maximal activation at low speed (0.25 m/sec), augmentation of neuronal activity only at high treadmill speed (0.77 m/sec), and a linear increase. A smaller fraction of NRO and NRP serotonergic neurons (6 of 27) also responded to hypercarbic ventilatory challenge with increased firing rates. The magnitude of neuronal response was dependent upon the fraction of inspired CO2 and was related to ventilatory motor output, specifically, inspiratory amplitude. A subgroup of neurons responsive to hypercarbia in wakefulness demonstrated significant reductions in neuronal response to hypercarbia in slow-wave sleep. Finally, unit activity for 12 of 29 cells increased in response to spontaneous feeding, displaying two distinct patterns of neuronal response in relation to onset and termination of feeding: rapid activation and deactivation versus a gradual increase and decrease. More than half of the cells studied under all three conditions were responsive to more than one motor task. These results indicate that serotonergic caudal raphe neurons are responsive to specific motor system challenges, with many neurons responsive to multiple motor tasks, and that the responsiveness of serotonergic neurons to at least one motor task, hypercarbic ventilatory challenge, is state dependent.

Effects of the putative 5-hydroxytryptamine1A antagonists BMY 7378, NAN 190 and (-)-propranolol on serotonergic dorsal raphe unit activity in behaving cats.

Recent evidence from our laboratory has demonstrated that blockade of somatodendritic 5-hydroxytryptamine (5-HT)1A autoreceptors by systemic administration of spiperone increases the firing rate of central serotonergic neurons in awake cats. The present study examines the effects of three other putative 5-HT1A antagonists (BMY 7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5]decane-7,9-dione), NAN 190 [1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl]piperazine) and (-)-propranolol) on the single-unit activity of serotonergic neurons recorded in the dorsal raphe nucleus of free-moving cats. Systemic administration of the phenylpiperazine derivatives BMY 7378 (5-100 micrograms/kg i.v.) and NAN 190 (5-250 micrograms/kg i.v.) produced a rapid, dose-dependent inhibition of neuronal activity with BMY 7378 being approximately twice as potent as NAN 190 (ED50 = 15.3 micrograms/kg vs. 34.2 micrograms/kg). The suppression of neuronal activity produced by both compounds was greatly attenuated by spiperone (1 mg/kg i.v.). Systemic administration of (-)-propranolol (2 and 4 mg/kg i.v.) produced a modest suppression of serotonergic neuronal activity which did not appear to be dose-related. The ability of BMY 7378, NAN 190 and (-)-propranolol to block the suppression of neuronal activity produced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a selective 5-HT1A agonist, was also examined. Pretreatment with these compounds had no significant effect on the inhibitory response of serotonergic neurons to 8-OH-DPAT challenge. These results indicate that BMY 7378 and NAN 190 act as agonists rather than antagonists at the somatodendritic 5-HT1A autoreceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

The social context for risky sexual behavior among adolescents.

This study supports a model of adolescents' risky sexual behavior in which this behavior is seen as a product of the same peer and family factors which influence a wide range of problem behaviors. The Patterson et al. (1992) model of peer and parental factors associated with adolescents' sexual risk-taking behavior was tested on three independent samples of adolescents, ages 14 through 18. Adolescents whose peers were reported to engage in diverse problem behaviors were more likely to engage in risky sexual behavior. Poor parental monitoring and parent-child coercive interactions were associated having deviant peers, and poor parental monitoring also had a direct relationship to risky sexual behavior. Family involvement was associated with fewer parent-child coercive interactions. Less availability of parental figures in the family was directly associated with risky sexual behavior and was also associated with poorer parental monitoring.