Methods of changing patterns of substance use among individuals with co-occurring schizophrenia and substance use disorder.

Individuals with a severe mental illness and substance use disorder tend to have medical and social problems and to make slower progress in treatment than those who have either disorder alone. Nevertheless, little attention has been paid to the discovery of effective methods of modifying substance use in the severely mentally ill (SMI). The purpose of this study was to collect qualitative data as a way to help identify techniques that might help to change patterns of substance use in the SMI. The participants were 21 men and women who were psychiatric clinic outpatients and who had a current schizophrenia spectrum diagnosis. A total of 18 participants had a lifetime diagnosis of alcohol abuse or dependence, and 21 lifetime other drug diagnoses were recorded for the sample. These individuals participated in focus group discussions about topics related to substance use and people's experiences with trying to quit. The results showed that participants identified several therapeutic and extratherapeutic factors that helped them to initiate and maintain changes in their substance use, as well as factors that hindered change. The findings are related to knowledge about the effectiveness of substance use disorder treatment techniques in general, and implications of the data are discussed for the conduct of integrated treatment of individuals with severe mental illness and a substance use disorder.

Decisional balance regarding substance use among persons with schizophrenia.

State-of-the-science treatment of substance abuse relies on decisional balance activities (weighing pros and cons of continued substance use) to enhance motivation for change. Few data are available regarding the feasibility of these activities among persons dually diagnosed with schizophrenia and substance use disorder. To address this lacuna in the literature, we completed focus groups with 21 participants, all of whom had a schizophrenia-spectrum diagnosis and lifetime substance abuse or dependence. These key informants discussed the pros and cons of substance use as well as the pros and cons of quitting in response to a structured group interview. Our qualitative data indicate that persons living with schizophrenia can generate rich and diverse decisional balance information. We describe salient themes, contrast complementary perspectives (i.e., the pros of using and cons of quitting), and suggest treatment implications based on these findings.

Presynaptic or postsynaptic location of receptors for angiotensin II and substance P in the medial solitary tract nucleus.

1. Microinjection of angiotensin (Ang) II or substance P (SP) into the medial nucleus tractus solitarii (nTS) produces similar decreases in arterial pressure and heart rate. We previously reported that some medial nTS neurons responsive to SP were also excited by Ang II, and that Ang II increased the release of SP from medulla slices. Both electrophysiological and anatomic data suggest that the cardiovascular effects of these peptides may be mediated by a common neuronal pathway consisting of SP-containing vagal afferent fibers with presynaptic Ang II receptors that innervate medial nTS neurons with SP receptors. To evaluate the validity of this model, we established the presynaptic or postsynaptic location of the receptors for Ang II and SP that mediate excitation of medial nTS neurons by determining the capacity of each peptide to activate the cell before and after blocking synaptic transmission in rat dorsal medulla slices. 2. Extracellular recordings were obtained from 55 medial nTS neurons responsive to Ang II or SP in 400-microns horizontal slices of the dorsal medulla. Neuronal excitation by Ang II and SP was tested before, during, and after reversal of synaptic blockade with low-Ca2+ (0.2 mM), high Mg2+ (5 mM) artificial cerebrospinal fluid (aCSF). Elimination of synaptically evoked short latency responses of the neuron to current pulses applied to afferent fibers in the solitary tract (TS) documented blockade of synaptic transmission by low-Ca2+ aCSF. In most cases, the basal firing rate of the cell increased slowly during perfusion with low-Ca2+ aCSF and stabilized after approximately 30 min at a higher level of spontaneous activity. Responses to the peptides and TS stimulation were also documented after synaptic blockade had been reversed by adding aCSF containing 2-mM Ca2+. 3. Of the 55 medial nTS neurons, 41 were responsive to Ang II; whereas, 50 of the 55 cells were responsive to SP. The neurons were divided into three subgroups on the basis of their responsiveness to Ang II and SP. Although most neurons were responsive to both Ang II and SP (n = 36), five other cells were excited only by Ang II, and 14 neurons were activated only by SP. Of the 55 neurons, 26 were also responsive to L-glutamate: 14 of 17 cells responsive to both Ang II and SP, all 5 neurons excited by Ang II but not by SP, and 7 of 10 neurons responsive only to SP were also excited by L-glutamate. The latency of the action potentials evoked by TS stimulation was much shorter in those neurons responsive only to Ang II (3.6 ms) than in cells excited by both Ang II and SP (6.8 ms) or responsive only to SP (7.4 ms). 4. In 21 of the 36 medial nTS neurons responsive to both Ang II and SP, Ang II continued to excite the cell when synaptic responses to TS stimulation were prevented by low-Ca2+ aCSF, but had no effect on the firing rate of the other 15 neurons during synaptic blockade. Excitation induced by Ang II was also prevented in two of the five medial nTS neurons responsive only to Ang II when synaptic transmission in the slice was blocked. Low-Ca2+ aCSF failed to prevent excitation by SP or L-glutamate in all medial nTS cells responsive to these agonists (n = 50 and n = 26, respectively). In contrast to these observations in medial nTS neurons, Ang II-induced excitation was not altered during synaptic blockade in any of the six dmnX cells studied. No responses to SP or L-glutamate were blocked in dmnX neurons, as also seen in the medial nTS. 5. When all medial nTS neurons responsive to Ang II were examined, the latencies of the response to TS stimulation were significantly shorter in those neurons with presynaptic Ang II receptors than in the group of cells with postsynaptic receptors. In addition, neurons with presynaptic Ang II receptors were distributed differently within the medial nTS than cells with postsynaptic Ang II receptors.(ABSTRACT TRUNCATED)

Mechanisms of angiotensin-induced hypotension and bradycardia in the medial solitary tract nucleus.

The selective angiotensin (ANG) II antagonists losartan (AT1) and CGP-42112A (AT2) were used to determine the receptor subtype and neuronal pathways that mediate the hypotension and bradycardia produced by 200 fmol of ANG II microinjected into the dorsal medial nucleus tractus solitarii (NTS) or dorsal motor nucleus of the vagus (dmnX) in anesthetized rats. At dorsal medial NTS sites (0.3 mm below the surface) where L-glutamate microinjections produced maximal decreases in mean arterial pressure (MAP) and heart rate (HR), ANG II (200 fmol, 50 nl, n = 16) elicited hypotension (-22 +/- 1 mmHg) and bradycardia (-26 +/- 2 beats/min). Although L-glutamate also suppressed respiration, ANG II injections in the medial NTS did not alter respiration. Losartan injected at the medial NTS site caused a dose-dependent reduction of ANG II-induced decreases in MAP and HR. At 2 pmol, the AT1 antagonist attenuated the response to ANG II, whereas 100 pmol abolished the effects of ANG II microinjections. In contrast, the AT2 antagonist CGP-42112A (100 pmol) had no effect on the responses to ANG II. Neither ANG II antagonist altered the cardiovascular effects of L-glutamate injections. Losartan injected into the dmnX blocked hypotension and bradycardia produced by ANG II at that site but did not prevent responses to subsequent ANG II injections in the medial NTS.(ABSTRACT TRUNCATED AT 250 WORDS)

Morphology and projections of neurobiotin-labeled nucleus tractus solitarii neurons recorded in vitro.

The suitability of the anterograde tracer neurobiotin to provide information about the morphology and projections of extracellularly or intracellularly recorded medial nucleus tractus solitarii (nTS) neurons was evaluated in horizontally oriented rat dorsal medulla in vitro slices. After responsiveness to angiotensin (Ang) II, substance P (SP), and L-glutamate was evaluated, neurons were labeled by electrophoresis of neurobiotin at the recording site. Extracellular application (2 microA for 2 min) produced discrete injection sites (40-70 microns) with a small group of labeled neurons. Ejections into the solitary tract documented that the tracer was not taken up by axons traversing the injection site. Neuronal perikarya, primary and secondary dendrites, and axons exhibited a dense Golgi-like appearance, with well-defined dendritic spines and axonal varicosities. Dendritic or axonal processes could be followed for more than 1 mm from the cell soma in a 50 microns thick section, documenting the horizontal architecture of the medial nTS. Intracellular electrophoresis filled the soma, primary and secondary dendrites, and axons of neurons characterized for responsiveness to peptides, L-glutamate and solitary tract stimulation. The location within the nTS and axonal projections of neurons responsive to Ang II and SP appeared to differ from those of cells responsive to Ang II and L-glutamate. Thus, either extracellular or intracellular application of neurobiotin in the in vitro slice can reveal differences in axonal or dendritic targets of neuronal subgroups responsive to different neurotransmitters or peptides and provide evidence for the likely autonomic significance of the neurons.

The reliability of ERP components in the auditory oddball paradigm.

Nineteen adolescents (average age 15 years, 3 months) were tested and retested using a standard 40 target, auditory oddball ERP paradigm across an interval of 1 year, 10 months to determine reliability of the ERP components, both in terms of intersubject stability and score agreement and in terms of trait (between-session reliability) versus state (within-session reliability). Significant trait stability was found for the N100, P200, and P300 latencies (r = .48, .51, and .74, respectively), and for P300 amplitude (r = .62), supporting the P300 as a reliable measure, with the stability required for group research but not necessarily for clinical applications. Discussion and examples illustrate the application of reliability information to the planning and evaluation of ERP paradigms.

Receptor subtype that mediates the neuronal effects of angiotensin II in the rat dorsal medulla.

We have shown previously that many neurons in the caudal medial nucleus tractus solitarii (nTS) are excited by angiotensin (Ang) II. The selective Ang II receptor antagonists losartan (AT1; DuP 753) and CGP 42112A or PD 123177 (AT2) were used to evaluate the receptor subtype that mediates excitation of medial nTS neurons by Ang II (1 microM) in rat medulla in vitro slices. Neither losartan nor the AT2 antagonists altered the baseline firing of either Ang II-sensitive or Ang II-unresponsive neurons. However, in six cells with low-frequency spontaneous activity that remained above baseline after excitation by Ang II, subsequent administration of losartan reversed the firing pattern to the initial low-frequency activity. Losartan (10 microM) blocked the excitation by Ang II in 29 medial nTS neurons. The Ang II-induced excitation recovered from Type I blockade in 1 h. In contrast, both CGP 42112A (10 and 100 microM, n = 12) and PD 123177 (100 microM, n = 7) failed to block excitation by Ang II in all neurons tested. Furthermore, the AT2 antagonists were ineffective in preventing Ang II-induced neuronal excitation both when they were the first antagonist tested and when they were evaluated after the neuron had recovered from AT1 receptor blockade. These studies suggest that the Ang II-induced excitation of caudal medial nTS neurons is mediated by AT1 Ang II receptors.

Light microscopic localization of angiotensin II binding sites in canine medulla using high resolution autoradiography.

Angiotensin II (Ang II) produces dose-related, site-specific cardiovascular effects in the canine and rat dorsal medulla. Our previous studies suggested that Ang II binding sites are associated with presynaptic vagal afferent fibers in the nucleus tractus solitarii (nTS) and vagal efferent neurons in the dorsal motor nucleus of the vagus (dmnX). High resolution autoradiography now establishes the relationship of putative Ang II receptors to the cytoarchitecture of these nuclei. Sections of the canine medulla oblongata were processed for film or emulsion autoradiography with 0.3-1 nM 125I-Ang II. Quantitative densitometry of films before and after processing sections for emulsion coating confirmed no selective alteration in labeling. In emulsion coated sections, dense labeling was seen over the majority of the large perikarya and surrounding neuropil in the ventral dmnX. Bands of label overlaid vagal efferent fibers coursing ventrolaterally to exit the medulla. In the nTS, Ang II binding was restricted to regions with heavy vagal afferent innervation. In the dorsal nTS, label was distributed over both cell bodies and neuropil, with highest density capping the solitary tract. In the medial nTS, label was concentrated over perikarya, with scattered grains over the intervening neuropil. The discrete subnuclear association of Ang II binding sites in the dorsal medulla with vagal cells and fibers documents that Ang II receptors are present on both afferent vagal fibers and intrinsic medullary neurons, and reveals an anatomical substrate for the autonomic effects of Ang II in this region.

Pressor effect of centrally administered sodium chloride: role of the ventral third ventricle region and the area postrema.

To determine the site(s) responsible for the central cardiovascular effect of hypertonic saline, 0.2 ml of 1.5 M NaCl was administered to anesthetized dogs via three routes, a lateral ventricle, the third ventricle and the cisterna magna. Intracisternal administration of hypertonic NaCl produced much prompter pressor and tachycardic responses than did administration via the other two routes. Covering the ventral third ventricle region with a petroleum jelly plug had the effect of abolishing the pressor response to lateral ventricular hypertonic NaCl but did not modify the response to intracisternal hypertonic NaCl. By contrast, electrolytic lesion of the area postrema attenuated the rise in blood pressure produced by the intracisternal NaCl without affecting the response to lateral ventricular NaCl. These results indicate that at least two sites, the ventral third ventricle region in the hypothalamus and the area postrema in the lower brainstem, are responsible for the acute hypertension induced by an increase in NaCl concentration in the cerebrospinal fluid of the dog.

Neurophysiological responses to angiotensin-(1-7).

The aim of this study was to investigate the action of the heptapeptide angiotensin-(1-7) on the spontaneous activity of paraventricular neurons using microiontophoresis. Recent immunocytochemical investigations have shown that this product of angiotensin I is predominantly located in cells and fibers of the forebrain and brain stem. Our results show that most neurons in the paraventricular nucleus are excited by angiotensin-(1-7) at a dose of 50-80 nA. In comparison with angiotensin II or angiotensin III, the onset of response and the occurrence of the maximal effect were significantly delayed. With higher doses of angiotensin-(1-7), there was a decrease in latency and a dose-dependent increase in firing frequency. Of all the angiotensin compounds tested, angiotensin III was the most potent. Preliminary results obtained with an angiotensin antagonist show that the action of angiotensin II, angiotensin III, and angiotensin-(1-7) is blocked by the angiotensin receptor subtype 2 antagonist CGP 42112A. Because the angiotensin-(1-7) system in the brain is associated with central vasopressinergic pathways, vasopressin was tested in a similar way. Neurons in the paraventricular nucleus that were excited by iontophoretically applied angiotensins showed a weak response to vasopressin. Occasionally, a small excitatory action was observed. Our results support the hypothesis that the heptapeptide angiotensin-(1-7) is a biologically active neuropeptide. The data also suggest that amino terminal fragments of angiotensin II are not inactive degradation products.

Functional interactions between angiotensin II and substance P in the dorsal medulla.

Low doses of either angiotensin (Ang) II or substance P (SP) microinjected into the medial nucleus tractus solitarii (NTS) produce hypotension and bradycardia, mimicking activation of the baroreceptor reflex. Anatomical evidence suggests that Ang II binding sites in the medial NTS are located presynaptically on vagal afferent fibers that may contain SP and are codistributed with SP binding sites located postsynaptically on intrinsic medial NTS neurons. To evaluate whether the similar cardiovascular effects of Ang II and SP in the medial NTS could involve Ang II-evoked release of SP, we compared the effects of these peptides on the spontaneous activity of medial NTS neurons recorded in vitro and determined whether Ang II evoked release of SP from rat medulla slices. Both Ang II and SP (1 microM in artificial cerebrospinal fluid) excited 11 of 40 medial NTS neurons. In these cells, the peak response latency was significantly longer to Ang II than to SP (59.5 +/- 4.7 versus 26.5 +/- 2.4 seconds, p less than 0.0001). When rat medulla slices were perfused with Ang II (2 microM in Krebs' bicarbonate), release of SP immunoreactivity was increased by 400% over control perfusion with Krebs' solution alone (p less than 0.05). We have provided the first evidence for an excitatory action of Ang II on neurons in the NTS of the rat and for excitation by both Ang II and SP of a subset of neurons in the medial NTS. Moreover, we have shown for the first time that Ang II can stimulate the release of SP immunoreactivity from the brain.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II and angiotensin (1-7) excite neurons in the canine medulla in vitro.

Our group showed previously that the heptapeptide angiotensin (1-7) [Ang-(1-7)] is a bioactive product of the renin-angiotensin system, and produces dose-dependent cardiovascular effects similar to those evoked by Ang II when microinjected into the nucleus tractus solitarii (nTS) of the rat. The effects of Ang II were compared with those of Ang-(1-7) on single neuron activity recorded from the medial nTS or dorsal motor nucleus of the vagus (dmnX) in perifused horizontal slices of the canine dorsomedial medulla. Ang II excited 48% of 31 medial nTS neurons, but only activated 14% of 22 dmnX cells. Ang-(1-7) also excited half of the medial nTS cells and 14% of the dmnXl neurons. Although most medial nTS neurons excited by Ang II were also activated by Ang-(1-7), two cells were excited by Ang II but not by Ang-(1-7), and one cell was excited by Ang-(1-7) but not by Ang II. Because Ang-(1-7) lacks direct vasoconstrictor effects, neurons in the dorsomedial medulla may have different receptor characteristics than peripheral tissues. The observation of a few medial nTS neurons excited by only one Ang peptide suggests that there may be a separate Ang-(1-7) receptor that participates in the physiological effects of Ang peptides mediated by the brain.

Pathways of angiotensin formation and function in the brain.

New findings from this laboratory suggest that fragments of angiotensin derived from the amino (N-)terminus are biologically active end products of the renin-angiotensin system. In vitro and in vivo experiments revealed that the heptapeptide angiotensin-(1-7) [Ang-(1-7)] is a major endogenous product of the renin-angiotensin system cascade in the brains of rats and dogs. Additional studies with enzyme inhibitors showed that Ang-(1-7) is produced directly from angiotensin I by an enzyme other than the angiotensin converting enzyme. Immunocytochemical fibers within the hypothalamo-neurohypophyseal vasopressinergic system of the rat. Although Ang-(1-7) is as potent as angiotensin II (Ang II) in stimulating release of vasopressin from superperfused hypothalamo-neurohypophyseal explants, the heptapeptide has no dipsogenic or vasoconstrictor activity. In contrast, Ang-(1-7) mimics the effects of Ang II in augmenting the intrinsic discharge rate of neurons within the vagal-solitary complex and in causing monophasic depressor responses after microinjection into the medial region of the nucleus tractus solitarii. The evidence obtained in these experiments suggests novel mechanisms for the generation of angiotensin peptides in the brain. Additionally, the findings suggest that some of the biological actions ascribed to Ang II might be conveyed by the endogenous production of other angiotensin peptides that are generated by enzymatic pathways alternate to those described in the peripheral circulation.

The canine nucleus tractus solitarii: light microscopic analysis of subnuclear divisions.

The nucleus tractus solitarii (nTS) is a complex structure situated in the dorsal medulla oblongata. This region receives primary visceral and gustatory sensory afferent fibers and has widespread interconnections with brainstem structures, hypothalamus, and limbic forebrain. In both rat and cat distinct subnuclei correlate with specific functions of the nTS. Since the canine model is used extensively for physiological study and evidence from this laboratory supports a critical role for the canine nTS in cardiovascular function, we examined its morphological organization. Light microscopic analysis of cellular and fiber patterns of the nTS revealed nine discrete regions based on cytoarchitecture: the commissural, lateral, ventral, dorsal, intermediate, interstitial and medial subnuclei, the subnucleus gelatinosa, and the dorsal parasolitary region. Analysis of each subnucleus revealed that both the lateral and ventral subnuclei contained two distinct neuronal groups based on cell size. Neurochemical and functional correlates are being provided by ongoing analyses of each subnucleus of the nTS.

Distribution of catecholaminergic neuronal systems in the canine medulla oblongata and pons.

The distribution of catecholamine-containing neurons, fibers, and varicosities in the brainstem of both adult and juvenile dogs was mapped in detail with glyoxylic acid histofluorescence. Four separate groups of catecholamine-fluorescent neurons were identified within the canine medulla and pons in locations comparable to the A1, A2, A5, and A6 regions reported in other species. However, aspects of the pattern and density of the catecholaminergic neuronal systems appeared to be unique to the dog. The A1 neurons of the caudal ventrolateral medulla were much more scattered than in rats or rabbits, but relatively similar to cats. In the A2 region of the dorsomedial medulla, catecholaminergic cells and fibers were uniquely distributed compared to other species: fluorescent neurons were scattered only within the dorsal motor nucleus of the vagus, and a distinctive pattern of fibers and varicosities outlined the nucleus of the solitary tract and dorsal motor nucleus of the vagus. The A5 neurons of the rostral ventrolateral medulla appeared at the rostral limit of the A1 region. Fluorescent A5 cells were more sparse than in rats or primates, and were patterned similarly to cats and rabbits. The canine A6 region contained the most extensive and dense grouping of catecholamine neurons and was similar in pattern to the rabbits but less extensive than that seen in cats or primates. An ascending catecholaminergic fiber pathway was traced through the central tegmental field of the canine medulla and pons, with features similar to the primate. The present study provides the first description of the catecholaminergic neuronal systems of the canine medulla.

Neuronal responses to angiotensin II in the in vitro slice from the canine medulla.

The present studies utilized the in vitro slice preparation of the canine dorsomedial medulla, which we have recently developed, to obtain direct evidence for the effects of angiotensin II (Ang II) on the activity of single neurons in this region. Horizontally oriented slices (300 micron) containing the area postrema, nucleus tractus solitarii (NTS), and dorsal motor nucleus of the vagus were perifused with oxygenated artificial cerebrospinal fluid. The effects of microdrop application of Ang II and its antagonist [Sar1,Thr8]Ang II on spontaneous firing rate were determined in 27 extracellularly recorded neurons. Ang II substantially increased the firing rate of 13 neurons located in the medial NTS, but it did not alter the spontaneous activity of the remaining 14 neurons. In most cases Ang II elicited a slowly developing, prolonged excitatory response. The effects of both Ang II and [Sar1,Thr8]Ang II were tested in 13 neurons. [Sar1,Thr8]Ang II produced a short latency, brief excitation in three neurons, marked inhibition of spontaneous firing in two cells, and no effect on the other eight neurons. Administration of [Sar1,Thr8]Ang II blocked the excitatory effects of subsequent administration of Ang II in three neurons. To our knowledge, these observations provide the first evidence for direct actions of both Ang II and [Sar1,Thr8]Ang II on neurons in the canine NTS and for the specificity of the neuronal effects of Ang II as documented by blockade of the excitatory response to Ang II by [Sar1,Thr8]Ang II.

Effect of area postrema lesion on low-frequency arterial pressure oscillations in dogs.

To explore the possibility that chronic inactivation of the area postrema (AP) may alter the frequency distribution of oscillations in blood pressure, the power spectra for mean arterial pressure (MAP) were evaluated in conscious dogs before and after heat coagulation (n = 4) or sham lesions (n = 6) of the AP. No significant changes in MAP were observed in either group of dogs after surgery. Tachycardia was seen in AP-lesioned animals after surgery; no consistent changes in heart rate were found in sham-lesioned dogs. Spectra were averaged to provide a group spectral estimate for the AP-lesioned and sham-lesioned groups, respectively, for each experimental period. In the sham-lesioned group a variance peak was observed at approximately 0.03 Hz both before and after surgery. The same peak was seen in the AP-lesioned group during the control period but disappeared following AP lesion, apparently because a greater proportion of the variance was shifted toward frequencies below 0.03 Hz. In addition, a peak related to respiratory rate was present in both groups before surgery but was selectively abolished by AP lesion. AP lesion also substantially reduced the power associated with frequencies between 0.1 and 0.4 Hz. The use of spectral analysis has allowed us to demonstrate that a low-frequency oscillation of MAP in conscious, resting dogs requires the integrity of the AP and that the 0.1- to 0.4-Hz components of the variability of MAP are attenuated after removal of the AP.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of area postrema pressor mechanisms in the regulation of arterial pressure.

This article discusses the data which established that angiotensin II modulates the tonic and reflex control of cardiovascular function by actions on the nuclear regions of the dorsal medulla oblongata. Although physiological evidence for the modulatory actions of angiotensin II in structures of the lower brainstem has been gathered over the past 16 years, only the recent application of new neurobiological techniques has allowed a more definitive understanding of its role. The identification of high affinity angiotensin II binding sites within the parenchyma of the area postrema with the technique of in vitro receptor autoradiography has provided anatomical validity for a role of angiotensin II in the central nervous system. The added discovery of angiotensin II binding sites in subnuclear components of the nucleus tractus solitarii and the motor nucleus of the tenth cranial nerve provides additional information on the various mechanisms through which angiotensin II may affect the intrinsic activity of the brainstem neuronal circuits involved in the integration of baroreceptor and sensory visceromotor function.

Pressor responses of angiotensin II microinjected into the dorsomedial medulla of the dog.

Angiotensin II (Ang II) was injected into regions of the dorsomedial medulla of dogs where both specific Ang II binding and neural elements containing this peptide are found. Picomole amounts of the peptide were delivered simultaneously from a linear array of 3 micropipettes with tips positioned concurrently in either the area postrema (ap), nucleus tractus solitarii (nTS), dorsal motor nucleus of the vagus (dmnX), or hypoglossal nucleus (nXII). Significant increases in blood pressure occurred with Ang II injections into the medial nTS (+12 +/- 2 mm Hg), the ap(+9 +/- 3 mm Hg), and the nXII (+6 +/- 2 mm Hg). In both the medial nTS and the nXII, the pressor responses were accompanied by significant increases in heart rate (+13 +/- 3 beats/min and +8 +/- 3 beats/min, respectively). Ang II injected into the dmnX did not produce consistent effects on blood pressure or heart rate. These data demonstrate that unilateral injections of picomole amounts of Ang II produce changes in blood pressure and heart rate which involve neural elements in the ap and medial nTS.