Evidence for involvement of ventral tegmental area cyclic AMP systems in behavioral sensitization to psychostimulants

The present study investigated the role of ventral tegmental area (VTA) cyclic AMP (cAMP) systems in the behavioral sensitivity to psychostimulants in male Sprague-Dawley rats. Bilateral microinjections of cholera toxin (CTX) into the VTA (50-500 ng/500 nl/side) dose-dependently sensitized animals to the locomotor stimulant effects of systemic d-amphetamine, cocaine and apomorphine, but were without effects on morphine-induced locomotion 24 hr after microinjection. The CTX-induced behavioral sensitization to amphetamine was even greater 72 hr after microinjection, but was no longer present 14 days after intra-VTA CTX pretreatment. Coadministration of the cAMP-dependent protein kinase inhibitor H8 into the VTA blocked CTX-induced sensitization to amphetamine, suggesting that the sensitization is dependent on phosphorylation events in the VTA mediated by cAMP-dependent protein kinase. Pretreatment with CTX did not enhance amphetamine-induced dopamine release in the nucleus accumbens relative to saline controls 24 hr after microinjection. A single bilateral injection of d-amphetamine into the VTA (5 micrograms/side) produced a significant sensitization to systemic amphetamine challenge 72 hr later, and this effect was also blocked by coadministration of H8 into the VTA. These results extend previous studies which have established the importance of the VTA in the development of behavioral sensitization and suggest that cAMP systems may play a crucial role in this neuroadaptive process.     

SR 48692, a non-peptide neurotensin receptor antagonist differentially affects neurotensin-induced behaviour and changes in dopaminergic transmission

Unilateral microinjection of neurotensin in the ventral tegmental area of the rat (2.5 micrograms/0.5 microliter) produced behavioural excitation illustrated by contralateral circling. Given orally, SR 48692, a selective and potent non-peptide neurotensin receptor antagonist, significantly reduced these rotations with a triphasic dose-effect relationship. Inhibition occurred at 0.12 mg/kg; further increases in dose up to 2.5 mg/kg produced no significant antagonism, then at doses > or = 5 mg/kg, a second phase of antagonism was observed. Bilateral injection of neurotensin (0.5 microgram each side) into the nucleus accumbens antagonized the increase in locomotor activity following intraperitoneal injection of amphetamine. Given orally, SR 48692 reduced dose-dependently (0.1-1 mg/kg) these intra-accumbens neurotensin effects. Using high pressure liquid chromatography with electrochemical detection, we showed that microgram amounts of neurotensin injected into the ventral tegmental area increased dihydroxyphenylacetate/dopamine ratios in the nucleus accumbens. Using in vivo voltammetry techniques, we found that the injection of nanogram and picogram amounts of neurotensin in the ventral tegmental area stimulated dopamine efflux in the nucleus accumbens. None of these biochemical changes were affected by SR 48692 (0.1-10 mg/kg). These results indicate complex interactions between neurotensin and the mesolimbic dopamine system. More particularly, the differential ability of SR 48692 to affect neurotensin-evoked behavioural versus biochemical changes supports the concept of neurotensin receptor heterogeneity.     

Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity

Motor activity elicited pharmacologically from the nucleus accumbens by the mu-opioid receptor agonist D-Ala-Tyr-Gly-NMePhe-Gly-OH (DAMGO) is augmented in rats sustaining dopamine depletions. GABAergic projections from the nucleus accumbens to ventral pallidum and ventral tegmental area (VTA) are involved because stimulation of GABAB receptors in the VTA (by baclofen) or GABAA receptors in the ventral pallidum (by muscimol) inhibit the motor response induced by the microinjection of DAMGO into the nucleus accumbens. The present study was done to determine which of these projections is mediating the augmented DAMGO-induced motor activity that follows 6-hydroxydopamine lesions of the nucleus accumbens. The inhibition of DAMGO-induced activation by pallidal injections of muscimol was markedly attenuated in lesioned animals, whereas the inhibition by VTA injections with baclofen was greatly enhanced. A similar switch in emphasis from pallidal to mesencephalic efferents was not observed for dopamine-induced motor activity, because muscimol microinjections inhibited the response elicited by dopamine microinjection into the nucleus accumbens in all subjects. The stimulation of mu-opioid receptors in the ventral pallidum also elicits motor activation, and this is blocked by baclofen microinjection into the VTA. However, after dopamine depletion in the nucleus accumbens, baclofen in the VTA was ineffective in blocking the motor response by DAMGO in the ventral pallidum. These data reveal that dopamine depletion in the nucleus accumbens produces a lesion-induced plasticity that alters the effect of mu-opioid receptor stimulation on efferent projections from the nucleus accumbens and ventral pallidum.     

Changes in gastric mucosa and Helicobacter pylori infection in young health volunteers

The effect of microinjection of a GABAB receptor agonist, baclofen, into the ventral tegmental area on the rewarding effect of morphine was investigated using the conditioned place preference paradigm in rats. Morphine (1-8 mg/kg, s.c.) caused a dose-related place preference for the drug-associated place. In contrast, microinjection of baclofen (0.1-1 nmol/side) into the ventral tegmental area did not produce a significant preference for either compartment of the test box. Pretreatment with baclofen (0.1-1 nmol/side) into the ventral tegmental area dose dependently suppressed the morphine (8 mg/kg, s.c)-induced place preference. This suppression of the morphine (8 mg/kg, s.c.)-induced place preference by baclofen (1 nmol/side), but not with the GABAA receptor antagonist bicuculline (1 nmol/side). The present results suggest that a decrease in GABAB neurotransmission in the ventral tegmental area, which may be produced via inhibition of a tonic GABAergic input by morphine, may be involved in the expression of the rewarding effect of morphine.     

Subpallidal outputs to the nucleus accumbens and the ventral tegmental area: anatomical and electrophysiological studies

The goal of this study was to investigate the functional organization of the subpallidal-->accumbens direct and indirect feedback loops by both anatomical and electrophysiological methods. The results of the dextran-conjugated rhodamine injections into the subpallidal area has shown three distinct projections: (1) a substantial pathway from the subpallidal area to the ventral tegmental area, (2) a more diffuse rostral projection from the subpallidal area to the core area of the nucleus accumbens, and (3) a sparse pathway projecting rostrodorsally from the subpallidal area toward the thalamic regions. Electrical or chemical stimulation of the subpallidal region, which was studied by the axonal tracer, evoked inhibitory responses in the majority (60 and 80%, respectively) of the accumbens and ventral tegmental area neurons in a standard extracellular recording study. Less than 1/3 of the accumbens or ventral tegmental area cells showed an increase in the mean firing rate. The majority (77.5%) of all responded neurons had a latency of less than 10 ms. Furthermore, injection of glutamate into the subpallidal area not only altered the firing pattern of the accumbens neurons, but also attenuated their excitatory responses elicited by the electrical stimulation of the ventral subiculum. Our results indicate that the subpallidal area plays a predominantly inhibitory role in the ventral tegmental area-accumbens-subpallidal circuitry, presumably by its GABAergic projections, and may also modulate subicular input into the nucleus accumbens.     

Beta-endorphin response to exercise. An update

Opioid receptor subtype antagonists differentially alter food intake under deprivation (24 h), glucoprivic (2-deoxy-D-glucose, 500 mg/kg, i.p.) or palatable (10% sucrose) conditions with mu (beta-funaltrexamine) and kappa (nor-binaltorphamine), but not delta1 ([D-Ala2,Leu5,Cys6]enkephalin) opioid antagonists reducing each form of intake following ventricular microinjection. Both mu and kappa opioid antagonists microinjected into either the hypothalamic paraventricular nucleus or the nucleus accumbens reduce intake under deprivation and glucoprivic conditions. Palatable intake is reduced by both antagonists in the paraventricular nucleus, but only mu antagonists are active in the accumbens. Food intake is stimulated by mu and delta, but not kappa, opioid agonists microinjected into the ventral tegmental area. The present study examined whether food intake under either deprivation, glucoprivic or palatable conditions was altered by bilateral administration of general (naltrexone), mu, kappa, delta1 or delta2 (naltrindole isothiocyanate) opioid antagonists into the ventral tegmental area. Deprivation (24 h)-induced feeding was significantly reduced by high (50 microg), but not lower (10-20 microg) doses of naltrexone (21%), and by delta2 (4 microg, 19%) antagonism in the ventral tegmental area. 2-Deoxy-D-glucose (500 mg/kg, i.p.)-induced hyperphagia was significantly reduced by high (50 microg), but not lower (20 microg) doses of naltrexone (64%), and by delta2 (4 microg, 27%) antagonism in the ventral tegmental area. Sucrose (10%) intake was significantly reduced by naltrexone (20-50 microg, 25-39%) and delta2 (4 microg, 25%) antagonism in the ventral tegmental area. Neither mu, kappa nor delta1 antagonists were effective in reducing any form of intake following microinjection into the ventral tegmental area. These data indicate that the ventral tegmental area plays a relatively minor role in the elicitation of these forms of food intake, and that delta2, rather than mu, kappa or delta1 opioid receptors appear responsible for mediation of these forms of intake by this nucleus.     

A heroin-, but not a cocaine-expecting, self-administration state preferentially alters endogenous brain peptides

The effects of L-type voltage-dependent Ca2+ channel blockers on apomorphine, bromocriptine and morphine-induced changes in locomotor activity were examined in mice. Apomorphine (4 mg/kg) and morphine (20 mg/kg) produced locomotor stimulation. Bromocriptine (8 mg/kg) produced a biphasic effect on motor behaviour, an early depressant phase, followed by locomotor stimulation. Amlodipine (2.5 mg/kg), nicardipine (10 mg/kg), diltiazem (10 mg/kg) and verapamil (10 mg/kg), which by itself did not affect locomotor activity, inhibited the stimulant phase of bromocriptine without altering the depressant phase, while they did not affect apomorphine- and morphine-induced locomotor stimulation. Apomorphine, bromocriptine and morphine-induced locomotor stimulation was decreased by SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7- ol) (0.05 mg/kg) or haloperidol (0.1 mg/kg). These results indicate that L-type voltage-dependent Ca2+ channels are involved in the motor stimulant effect of bromocriptine, but not in apomorphine- and morphine-induced locomotor stimulation. The effects of Ca2+ channel blockers on the dopaminergic system appears not to be directly related to dopamine receptor blockade.     

Loss of haloperidol induced gene expression and catalepsy in protein kinase A-deficient mice

The antipsychotic drug, haloperidol, elicits the expression of neurotensin and c-fos mRNA in the dorsal lateral region of the striatum and produces an acute cataleptic response in rodents that correlates with the motor side effects of haloperidol in humans. Mice harboring a targeted disruption of the RIIbeta subunit of protein kinase A have a profound deficit in cAMP-stimulated kinase activity in the striatum. When treated with haloperidol, RIIbeta mutant mice fail to induce either c-fos or neurotensin mRNA and the acute cataleptic response is blocked. However, both wild-type and mutant mice become cataleptic when neurotensin peptide is directly injected into the lateral ventricle, demonstrating that the kinase deficiency does not interfere with the action of neurotensin but rather its synthesis and release. These results establish a direct role for protein kinase A as a mediator of haloperidol induced gene induction and cataleptic behavior.     

Evidence for the involvement of phospholipase A2 mechanisms in the development of stimulant sensitization

Evidence suggests that phospholipase A2 (PLA2) activation is involved in numerous neuroplastic phenomena, including long-term potentiation. Considering the pharmacological similarities between long-term potentiation and stimulant sensitization, it seems possible that PLA2 inhibition activity also might have a role in the induction of stimulant sensitization. In this study, we have investigated whether PLA2 inhibition, by quinacrine, has any effects on stimulant-induced behavioral sensitization. Both locomotor and stereotypic behavioral sensitization were dose-dependently blocked in rats pretreated with quinacrine (8-25 mg/kg i.p.) 15 min before cocaine (30 mg/kg i.p.), when tested with cocaine (15 mg/kg i.p) 72 hr later. Similar results also were found with d-amphetamine (2 mg/kg i.p.) sensitization using a 10-day treatment regimen with testing on day 11. The ability of PLA2 activation, by melittin, to produce cocaine sensitization also was tested. Local injections of melittin (0.1 microgram/0.4 microliter) into the ventral tegmental area sensitized the subsequent stimulation of locomotor activity, stereotypy and nucleus accumbens dopamine release by cocaine, when tested 72 hr later. Local injections of melittin (0.1-1.0 microgram/0.8 microliter) into the nucleus accumbens had a moderate sensitizing effect on locomotion. Quinacrine (16 mg/kg) pretreatment 45 min before intraventral tegmental area melittin injection significantly decreased melittin-induced sensitization of the locomotor and stereotypy response to cocaine. These results indicate that PLA2 activation may play a role in the induction of stimulant sensitization. It is proposed that PLA2 activity in mesolimbic dopamine neurons, at the level of the cell bodies and perhaps the nerve terminals, is involved in the biochemical mechanisms mediating the development of stimulant sensitization.     

N-methyl-D-aspartate receptor antagonism in the ventral tegmental area diminishes the systemic nicotine-induced dopamine release in the nucleus accumbens

Systemic nicotine enhances burst firing of dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens, mainly via stimulation of nicotinic acetylcholine receptors in the ventral tegmental area. Given that both the neuronal activity of mesolimbic dopamine neurons and terminal dopamine release are regulated by excitatory amino acid inputs to the ventral tegmental area and that nicotine facilitates glutamatergic transmission in brain, we investigated the putative role of ionotropic glutamate receptors within the ventral tegmental area for the effects of nicotine on dopamine release in the nucleus accumbens using microdialysis, with one probe implanted in the ventral tegmental area for drug application and another in the ipsilateral nucleus accumbens for measuring dopamine, in awake rats. Systemic nicotine (0.5 mg/kg, s.c.) and infusion of nicotine (1.0 mM) into the ventral tegmental area increased dopamine output in the nucleus accumbens. Intrategmental infusion of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (0.1 mM) or N-methyl-D-aspartate (0.3 mM) increased accumbal dopamine release; these effects were antagonized by concomitant infusion of a selective antagonist at N-methyl-D-aspartate receptors, 2-amino-5-phosphonopentanoic acid (0.3 mM), and non-N-methyl-D-aspartate receptors, 6-cyano-7-nitroquinoxaline-2,3-dione (0.3 mM), respectively. Infusion of either antagonist (0.3 or 1.0 mM) into the ventral tegmental area did not affect basal dopamine levels, whereas infusion of 2-amino-5-phosphonopentanoic acid, but not 6-cyano-7-nitroquinoxaline-2,3-dione, starting 40 min before nicotine injection dose-dependently attenuated the nicotine-induced increase in accumbal dopamine release. Concurrent intrategmental infusion of 2-amino-5-phosphonopentanoic acid and nicotine decreased nicotine-induced dopamine release in the nucleus accumbens. These results indicate that the stimulatory action of nicotine on the mesolimbic dopamine system is to a considerable extent mediated via stimulation of N-methyl-D-aspartate receptors within the ventral tegmental area.     

The pathways of cell death: oncosis, apoptosis, and necrosis

Differential pulse voltammetry was used to investigate the extracellular dopamine (DA) and DOPAC signal in the anterior part of nucleus accumbens (N.acc.) after microinjection of cholecystokinin (CCK) derivatives into the ventral tegmental area (VTA). Both the mixed CCK(A)/CCK(B) receptor agonist CCK-8s and the selective CCK(B) receptor agonist CCK-4 caused a dose-dependent increase in the DA signal after doses of 10 ng and 100 ng while CCK-8s had no effect on the DOPAC signal. The CCK(A) receptor antagonist L 364,718 (25 microg/kg i.p.) as well as the CCK(B) receptor antagonist L 365,260 (25 microg/kg i.p.) were administered prior to microinjection of 100 ng CCK-8s and L 365,260, but not L 364,718, completely inhibiting the DA increase produced by CCK-8s. Analysis of the tissue levels of DA and its main metabolites in the anterior part of N.acc. revealed no changes after CCK-8s microapplication into VTA. The presented data indicate a CCK(B) receptor-mediated increase in extracellular DA in the anterior N.acc. after microapplication of CCK derivatives into the VTA.     

Sensitization to morphine induced by viral-mediated gene transfer

Repeated administration of morphine sensitizes animals to the stimulant and rewarding properties of the drug. It also selectively increases expression of GluR1 (an AMPA glutamate receptor subunit) in the ventral tegmental area, a midbrain region implicated in morphine action. By viral-mediated gene transfer, a causal relation is shown between these behavioral and biochemical adaptations: Morphine's stimulant and rewarding properties are intensified after microinjections of a viral vector expressing GluR1 into the ventral tegmental area. These results confirm the importance of AMPA receptors in morphine action and demonstrate specific locomotor and motivational adaptations resulting from altered expression of a single localized gene product.     

Locomotor activation induced by infusion of endorphins into the ventral tegmental area: evidence for opiate-dopamine interactions

beta-Endorphin in nanomole quantities produced a stimulation of locomotor activity when infused into the region of the dopamine cell bodies of the ventral tegmental area (VTA) in rats. alpha-, gamma-, and des-Tyr-gamma-endorphin produced similar effects, but the D-alanine analogues of alpha and gamma-endorphin produced a larger and longer-lasting activation, presumably reflecting their resistance to degradation. This locomotor activation was reversible by pretreatment with naloxone and by destruction of the terminal projections of the mesocorticolimbic dopamine system originating in the VTA. These results demonstrate that locally infused endorphin can interact with the opioid receptors in the VTA, and they suggest a means by which endorphins activate limbic excitability.     

Mesencephalic microinjections of neurotensin-(1-13) and its C-terminal fragment, neurotensin-(8-13), potentiate brain stimulation reward

Using the curve shift method, we assessed the effects of ventromedial mesencephalic tegmental (VMT) microinjections of an equimolar concentration of neurotensin-(1-13) (NT-(1-13)) and of its C-terminal fragment, neurotensin-(8-13) (NT-(8-13)), on operant responding for rewarding electrical stimulation of the caudal mesencephalic central gray. The effects of NT-(1-13) and NT-(8-13) on brain stimulation reward (BSR) were also compared to those of systemically administered quinpirole (0.1 and 0.2 mg/kg, s.c.), a direct dopamine agonist, and GBR-12909 (10 and 20 mg/kg, i.p.), a selective dopamine uptake blocker. At the concentration injected, NT-(8-13) was as effective as NT-(1-13) at facilitating BSR, producing significant leftward shifts of the function relating the rate of responding to the stimulation frequency (R/F function); neither form of the peptide was effective when injected in regions dorsal to the VMT. Similarly, GBR-12909 produced a parallel leftward shift of the R/F function, but, unlike NT-(1-13), also significantly increased the asymptotic rates of responding. In contrast, the high dose of quinpirole produced non-parallel leftward shifts of the R/F function and suppressed the asymptote. The similarity between the effects of neurotensin and GBR-12909 on one hand, and the differences between those of neurotensin and quinpirole on the other, suggest that activation VMT neurotensin receptors potentiate BSR by enhancing increases in dopamine neurotransmission that are contingent upon operant responding or rewarding brain stimulation, or both.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of knife-cut lesions of the medial forebrain bundle in self-stimulating rats.

Unilateral frontal-plane knife-cut lesions were made in the anterior medial forebrain bundle ipsilateral to a lateral hypothalamic self-stimulation electrode. Behavioral effects of the knife cut on self-stimulation reward and operant performance capacity were measured via the reward summation function method. Knife cuts placed at the level of the anterior commissure were ineffective in altering reward or motor/performance capacity, whereas knife cuts just posterior in the caudal lateral preoptic area degraded reward and sometimes impaired motor/performance capacity. In a second experiment, knife cuts placed posterior to the ventral tegmental area were ineffective unless they intruded on the ventral tegmental area itself. Several small knife cuts placed just anterior to the ventral tegmental were effective in reducing self-stimulation reward. The results are discussed in terms of the anatomical substrate of lateral hypothalamic self-stimulation reward and as a first step in a larger mapping study. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Separation of hybridoma cells from their IgG product using aqueous two-phase systems

The cuneiform nucleus and the pedunculopontine tegmental nucleus have both been suggested as possible sites for the mesencephalic locomotor region (MLR), an area from which controlled stepping on a treadmill can be elicited following electrical or chemical stimulation in a decerebrate animal. It has been shown that excitotoxic lesions of the pedunculopontine tegmental nucleus impair neither spontaneous locomotion nor locomotion induced by stimulation of the nucleus accumbens. Excitotoxic lesions of the cuneiform nucleus have not previously been investigated. Rats received either bilateral ibotenate or sham lesions of the cuneiform nucleus combined with bilateral implantation of guide cannulae aimed at the nucleus accumbens. On recovery from surgery spontaneous locomotion was tested, followed by accumbens-stimulated locomotion. For nucleus accumbens stimulation, each rat received bilateral microinjection of each of three doses of d-amphetamine (10.0, 20.0 and 30.0 micrograms) and a vehicle only injection. Locomotor activity was recorded following the injection. In comparison to the sham-lesioned group, the ibotenate-lesioned group showed no differences in either spontaneous or amphetamine-induced locomotor activity. These results suggest that, like the pedunculopontine tegmental nucleus, the cuneiform nucleus is not involved in the direct mediation of spontaneous or accumbens-induced locomotion, and thus is very unlikely to be the anatomical substrate of the MLR. The role of the cuneiform nucleus in other types of behavioural control is discussed.     

Haloperidol induces persistent down-regulation of tyrosine hydroxylase immunoreactivity in substantia nigra but not ventral tegmental area in the rat

The dopamine antagonist haloperidol can cause tardive side-effects that may persist after the drug is withdrawn. We studied the time course of changes in dopaminergic neurons of the substantia nigra and ventral tegmental area following withdrawal of haloperidol. Rats received daily intraperitoneal injections of saline or haloperidol for eight weeks and were killed at two, four or 12 weeks after the final injection. Sections of substantia nigra and ventral tegmental area were processed for tyrosine hydroxylase immunohistochemistry. Quantitative morphometric analysis was carried out blinded in order to determine the number, cell body size and topography of tyrosine hydroxylase-positive cells, and the immunoreactive area of the substantia nigra and ventral tegmental area. In haloperidol-treated rats, tyrosine hydroxylase-positive cell counts were normal in ventral tegmental area but were decreased in substantia nigra by 34% at two weeks withdrawal and by 52% at four weeks withdrawal; cell counts were almost fully recovered by 12 weeks withdrawal. Cross-sectional area of tyrosine hydroxylase immunoreactivity within the substantia nigra demonstrated a similar pattern of reduction, with full recovery by 12 weeks withdrawal. Mean cell size, by contrast, was essentially unchanged at two and four weeks withdrawal, but was significantly decreased in sub-regions of substantia nigra at 12 weeks withdrawal. These results indicate that haloperidol can produce selective changes in midbrain dopamine neurons that persist long after discontinuation of the drug. This decrease in tyrosine hydroxylase-immunoreactive cell counts may play a role in the neurobiology of the persistent tardive syndromes associated with the use of neuroleptics.     

Increase of extracellular glutamate and expression of Fos-like immunoreactivity in the ventral tegmental area in response to electrical stimulation of the prefrontal cortex

Electrical stimulation of the medial prefrontal cortex caused glutamate release in the ventral tegmental area (VTA) of freely moving animals. Cathodal stimulation was given through monopolar electrodes in 0.1-ms pulses at an intensity of 300 microA and frequencies of 4-120 Hz. Glutamate was measured in 10-min perfusate samples by HPLC coupled with fluorescence detection following precolumn derivatization with o-phthaldialdehyde/beta-mercaptoethanol. The stimulation-induced glutamate release was frequency dependent and was blocked by the infusion of the sodium channel blocker tetrodotoxin (10 microM) through the dialysis probe. The stimulation also induced bilateral Fos-like immunoreactivity in ventral tegmental neurons, with a significantly greater number of Fos-positive cells on the stimulated side. These findings add to a growing body of evidence suggesting that the medial prefrontal cortex regulates dopamine release in the nucleus accumbens via its projection to dopamine cell bodies in the VTA.     

Role of the mesolimbic dopamine system in cardiovascular homeostasis. Stimulation of the ventral tegmental area modulates the effect of vasopressin on blood pressure in conscious rats

1. The possible role of the ventral tegmental area (VTA) and its dopaminergic projections in cardiovascular regulation is reviewed. 2. Our own work has shown that stimulation of the VTA by local microinjection of the substance P analogue DiMe-C7 caused an increase in blood pressure. The mechanism of the pressor response was an interaction of central dopaminergic activation, most likely at the level of the baroreflex, with the circulatory actions of vasopressin. 3. These findings are important for a possible role of the mesolimbic dopamine system in cardiovascular homeostasis. Several studies reviewed here show that neuronal activity of the VTA and its mesolimbic projections is altered by changes in blood pressure, salt and electrolyte balance, stress and food and water intake. 4. The VTA and mesolimbic dopamine system, while playing a widely accepted role in locomotor activity, cognition and reward mechanisms, may also be involved in the integration of sensory and behavioural information with cardiovascular homeostasis.