The rostromedial tegmental nucleus modulates the development of stress-induced helpless behavior.

A growing body of clinical and preclinical research suggests that structural and functional changes in the habenula, a component of the epithalamus, are associated with major depressive disorder. A major excitatory, efferent projection from the habenula targets the rostromedial tegmentum (RMTg), a mesopontine region that provides significant input to the ventral tegmentum and raphe nuclei. While the RMTg contributes to monoaminergic responses to aversive events, its role in stress-based animal models of depression has yet to be determined. In the present study, we test the hypothesis that the RMTg is a component of the circuitry mediating the development of a maladaptive behavior in which rats repeatedly exposed to inescapable footshock, fail to avoid or escape the same stressor when subsequently given the opportunity to do so. Excitotoxic lesions of the RMTg significantly diminished the frequency of these escape failures 24 h after exposure to inescapable footshock. Conversely, electrical stimulation of the Hb during the initial uncontrollable aversive event, a manipulation that enhances excitatory input to the RMTg, increased the number of trials in which subjects failed to escape an aversive stimulus when presented the option 24 h later. These complementary results provide evidence supporting a role for the RMTg in the expression of stress-induced helpless phenotype and are an important step in understanding the contribution made by this region to the development of depression-related maladaptive behaviors.

Chaotic versus stochastic dynamics: a critical look at the evidence for nonlinear sequence dependent structure in dopamine neurons.

The firing pattern of midbrain dopamine neurons is thought to have important behavioral consequences. Although these neurons fire regularly in vitro when deprived of their afferent inputs, they usually fire irregularly in vivo. It is not known whether the irregularity is functionally important and whether it derives from the intrinsic properties of dopamine neurons or network interactions. It is also not known whether the irregular firing pattern is fundamentally stochastic or deterministic in nature. Distinguishing between the deterministic nonlinear structure associated with chaos and other sources of structure including correlated noise is an inherently nontrivial problem. Here we explain the geometric tools provided by the field of nonlinear dynamics and their application to the analysis of interspike interval (ISI) data from midbrain dopamine neurons. One study failed to find strong evidence of nonlinear determinism, but others have identified such a structure and correlated it with network interactions.

SK Ca2+-activated K+ channel ligands alter the firing pattern of dopamine-containing neurons in vivo.

Apamin-sensitive, SK channels play an important role in generating the rhythmic firing patterns exhibited by midbrain dopamine neurons in vitro. However, their contribution to the firing properties of these cells in intact animals has yet to be determined. In the present series of experiments, extracellular single unit recording techniques were used to assess the central effects of prototypical SK channel ligands on the firing pattern of dopamine neurons in the substantia nigra of the chloral hydrate anesthetized rat. I.v. administration of the SK channel blocker apamin (0.4 mg/kg), increased bursting activity in approximately 50% of the dopamine neurons tested without altering average firing rate. The majority of these cells responded slowly to the effects of apamin, gradually transitioning from an irregular single spike to a phasic discharge composed of the same relative proportion of long (>or=three spike) and short (two spike) bursts as "natural" bursting activity recorded in drug naive animals. Local administration of apamin increased bursting activity in all cells tested. Systemic administration of the SK channel opener, 1-ethyl-2-benzimidazolinone (5-25 mg/kg) also had no effect on average firing rate but suppressed bursting activity and increased the precision of firing. The effects of 1-ethyl-2-benzimidazolinon on firing pattern were abolished when recording electrodes contained apamin (125 microM). These results suggest that SK channels actively contribute to the spontaneous firing patterns exhibited by dopamine neurons in vivo and provide additional support for the proposition that this channel could serve as a useful target for modifying their activity.

Scaling of prediction error does not confirm chaotic dynamics underlying irregular firing using interspike intervals from midbrain dopamine neurons.

Dopamine neurons in the substantia nigra pars compacta often fire in an irregular, single spike mode in vivo, and a similar firing pattern can be observed in vitro when small conductance calcium-activated potassium channel blockers are applied to the bath. It is not clear whether the irregular firing is due to stochastic processes or nonlinear deterministic processes. A previous study [Neuroscience 104 (2001) 829] used nonlinear forecasting methods applied to a continuous function derived from the interspike interval (ISI) data from irregularly firing dopamine neurons to show that the predictability scaled exponentially with forecast horizon and was consistent with nonlinear deterministic chaos. However, we show here that the observed exponential scaling is also consistent with a stochastic process, because it did not differ significantly from that of shuffled surrogate data. On the other hand, nonlinear forecasting directly from the ISI data using the package TISEAN provided some evidence for nonlinear deterministic structure in four of five records obtained in vitro and in two of nine records obtained in vivo. Although we cannot rule out a role for nonlinear chaotic dynamics in structuring the firing pattern, we suggest an alternate hypothesis that includes a mechanism by which the firing pattern can become more variable in the presence of a constant level of background noise.

Apamin-induced irregular firing in vitro and irregular single-spike firing observed in vivo in dopamine neurons is chaotic.

Dopamine neurons of the substantia nigra often fire action potentials irregularly in vivo, but in vitro fire in a regular, pacemaker-like firing pattern. Bath application of apamin, a blocker of calcium-activated potassium channels, can shift a dopamine neuron from pacemaker-like to irregular firing. To determine whether the irregular firing was caused by intrinsic cellular mechanisms rather than random synaptic input or some other form of noise, spike density functions of interspike interval records were analyzed using non-linear forecasting methods to quantify any non-linear (non-periodic) structure. Intrinsic cellular mechanisms are capable of producing chaotic firing, which is deterministic, non-linear, and loses predictability exponentially with increasing forecast time.To determine whether forecasting spike density functions could reliably measure predictability, forecasting was first applied to spike density functions produced by computer simulations of pacemaker-like, chaotic, and random firing, as well as pacemaker-like and chaotic firing that were randomly synaptically driven. Exponential loss of predictability was successfully detected in both chaotic and randomly driven chaotic firing. Predictability scaled faster than exponentially for random spiking, and linearly (slower than exponentially) for randomly driven pacemaker firing. The method was then applied to experimental records of apamin-induced irregular firing of rat dopaminergic neurons of the substantia nigra in vitro and in vivo. Exponential loss of predictability was detected in both cases, consistent with chaotic firing. Experimental records of pacemaker-like firing in vitro showed linear scaling, consistent with a randomly driven pacemaker. Several schemes for neural encoding of synaptic inputs have been suggested, such as rate codes or temporal codes. However, our results suggest that under some conditions, the irregular firing of dopamine neurons does not reflect the random temporal dynamics of its inputs, but rather the intrinsic, deterministic dynamics of dopamine cells themselves, under the tonic neuromodulatory influence of apamin in vitro and possibly that of an unidentified endogenous modulatory substance in vivo.

Afferent modulation of dopamine neuron firing patterns.

In recent studies examining the modulation of dopamine (DA) cell firing patterns, particular emphasis has been placed on excitatory afferents from the prefrontal cortex and the subthalamic nucleus. A number of inconsistencies in recently published reports, however, do not support the contention that tonic activation of NMDA receptors is the sole determinate of DA neuronal firing patterns. The results of work on the basic mechanism of DA firing and the action of apamin suggest that excitatory projections to DA neurons from cholinergic and glutamatergic neurons in the tegmental pedunculopontine nucleus, and/or inhibitory GABAergic projections, are also involved in modulating DA neuron firing behavior.

Pertussis toxin lesions of the rat substantia nigra block the inhibitory effects of the gamma-hydroxybutyrate agent, S(-)HA-966 without affecting the basal firing properties of dopamine neurons.

S(-)3-amino-1-hydroxypyrrolidone-2 (S(-)HA-966), a potent gamma-hydroxybutyrate-like drug, inhibits spontaneous firing and induces a pacemaker-like discharge pattern in nigral dopamine (DA)-containing neurons. Recent evidence has suggested that these effects could be mediated by GABAB receptors and, thus, is likely to involve G protein intermediaries. To test this hypothesis, extracellular single-unit recording techniques were used to assess the effects of S(-)HA-966 in animals that had received an intranigral injection of pertussis toxin (PT). Failure to respond to the inhibitory effects of apomorphine was taken as presumptive evidence that PT-sensitive G protein-coupled receptors had been inactivated. No significant differences were observed in the basal firing properties of DA cells recorded in control and PT-lesioned animals. However, in marked contrast to the inhibitory effects observed in uninjected and sham-lesioned animals, S(-)HA-966 significantly increased the firing rate of apomorphine-insensitive DA neurons in PT-lesioned rats. The excitatory effects of S(-)HA-966 were accompanied by a significant reduction in bursting activity and an increase in the regularity of firing. These data indicate that the inhibitory effects of S(-)HA-966 are mediated locally within the substantia nigra by a PT-sensitive substrate, presumably a G protein-coupled receptor.

Blockade of SK-type Ca2+-activated K+ channels uncovers a Ca2+-dependent slow afterdepolarization in nigral dopamine neurons.

Sharp electrode current-clamp recording techniques were used to characterize the response of nigral dopamine (DA)-containing neurons in rat brain slices to injected current pulses applied in the presence of TTX (2 microM) and under conditions in which apamin-sensitive Ca2+-activated K+ channels were blocked. Addition of apamin (100-300 nM) to perfusion solutions containing TTX blocked the pacemaker oscillation in membrane voltage evoked by depolarizing current pulses and revealed an afterdepolarization (ADP) that appeared as a shoulder on the falling phase of the voltage response. ADP were preceded by a ramp-shaped slow depolarization and followed by an apamin-insensitive hyperpolarizing afterpotential (HAP). Although ADPs were observed in all apamin-treated cells, the duration of the response varied considerably between individual neurons and was strongly potentiated by the addition of TEA (2-3 mM). In the presence of TTX, TEA, and apamin, optimal stimulus parameters (0.1 nA, 200-ms duration at -55 to -68 mV) evoked ADP ranging from 80 to 1,020 ms in duration (355.3 +/- 56.5 ms, n = 16). Both the ramp-shaped slow depolarization and the ensuing ADP were markedly voltage dependent but appeared to be mediated by separate conductance mechanisms. Thus, although bath application of nifedipine (10-30 microM) or low Ca2+, high Mg2+ Ringer blocked the ADP without affecting the ramp potential, equimolar substitution of Co2+ for Ca2+ blocked both components of the voltage response. Nominal Ca2+ Ringer containing Co2+ also blocked the HAP evoked between -55 and -68 mV. We conclude that the ADP elicited in DA neurons after blockade of apamin-sensitive Ca2+-activated K+ channels is mediated by a voltage-dependent, L-type Ca2+ channel and represents a transient form of the regenerative plateau oscillation in membrane potential previously shown to underlie apamin-induced bursting activity. These data provide further support for the notion that modulation of apamin-sensitive Ca2+-activated K+ channels in DA neurons exerts a permissive effect on the conductances that are involved in the expression of phasic activity.

Nifedipine blocks apamin-induced bursting activity in nigral dopamine-containing neurons.

Intrinsic sinusoidal oscillations in membrane potential, characteristic of nigral dopamine cells, are converted to plateau potentials following application of apamin, a potent antagonist of SK-type Ca2+-activated K+ channels. Blockade of these channels also changes neuronal firing pattern from a single-spike pacemaker discharge to a multiple spike bursting pattern. Nifedipine, a selective antagonist of L-type Ca2+ channels, blocks plateau potential generation; however, its effects on firing pattern have yet to be determined. In the present study, extracellular single unit recording techniques were used in conjunction with a brain slice preparation to determine whether nifedipine, in a concentration known to block plateau potential generation, also affects bursting activity. Nifedipine (30 microM) was equipotent in inhibiting the firing rate of control (51.2+/-10.8%) and apamin-treated (44.9+/-5.4%) neurons. Slow firing neurons (<2 Hz) were particularly sensitive to the inhibitory effects of the drug. Apamin-induced bursting was completely suppressed by nifedipine and accompanied by a significant increase in the regularity of firing. By contrast, pacemaker-like activity exhibited by control neurons was unaffected by the drug. These data demonstrate that the intrinsic plateau properties exhibited by DA neurons are responsible for the generation of phasic activity induced following blockade of apamin-sensitive Ca2+-activated K+ channels and provide further support for the involvement of an L-type Ca2+ conductance in mediating this type of activity.

Competitive NMDA receptor antagonists differentially affect dopamine cell firing pattern.

Alterations in the firing pattern of mesencephalic dopamine (DA) neurons appear to constitute a physiological mechanism through which these cells modify their effects on target neurons. Several lines of evidence suggest that the activity patterns exhibited by DA cells in vivo are contingent on tonic activation of N-methyl-D-aspartate (NMDA) receptors. In the present series of experiments, extracellular single unit recording techniques were used to assess the effects of the centrally acting, competitive NMDA receptor antagonists CGS-19755, (+/-)-CPP, NPC-12626 and NPC-17742 on the firing properties of nigral DA neurons in the chloral hydrateanesthetized rat. Each of the drugs tested produced a modest increase in firing rate accompanied by a significant regularization of neuronal firing pattern. Although the number of bursts and the percentage of spikes in bursts were reduced, the proportion of cells operationally defined as bursting was not appreciably altered. This appeared to be due to the ability of these drugs to reduce the number of spike doublets without affecting the incidence of longer bursts. Although generally consistent with the notion that NMDA receptors modulate DA neuronal firing pattern, the present data do not support the contention that tonic activation of these receptors is solely responsible for the expression of bursting activity in vivo.

Responses of rat substantia nigra dopamine-containing neurones to (-)-HA-966 in vitro.

1. Extracellular single unit recording techniques were used to compare the effects of (-)-3-amino-1-hydroxypyrrolidin-2-one ((-)-HA-966) and (+/-)-baclofen on the activity of dopamine-containing neurones in 300 microns slices of rat substantia nigra. Electrophysiological data were compared with the outcome of in vitro binding experiments designed to assess the affinity of (-)-HA-966 for gamma-aminobutyric acid (GABAB) receptors. 2. Bath application of (-)-HA-966 produced a concentration-dependent inhibition of dopaminergic neuronal firing (EC50 = 444.0 microM; 95% confidence interval: 277.6 microM - 710.1 microM, n = 27) which was fully reversible upon washout from the recording chamber. Although similar effects were observed in response to (+/-)-baclofen, the direct-acting GABAB receptor agonist proved to be considerably more potent than (-)-HA-966 (EC50 = 0.54 microM; 95% confidence interval: 0.44 microM - 0.66 microM, n = 29) in vitro. 3. Low concentrations of chloral hydrate (10 microM) were without effect on the basal firing rate of nigral dopaminergic neurones but significantly increased the inhibitory effects produced by concomitant application of (-)-HA-966. 4. The inhibitory effects of (-)-HA-966 were completely reversed in the presence of the GABAB receptor antagonists, CGP-35348 (100 microM) and 2-hydroxysaclofen (500 microM). Bath application of CGP-35348 alone increased basal firing rate. However, the magnitude of the excitation (9.2 +/- 0.3%) was not sufficient to account for the ability of the antagonist to reverse fully the inhibitory effects of (-)-HA-966. 5. (-)-HA-966 (0.1-1.0 mM) produced a concentration-dependent displacement of [3H]-GABA from synaptic membranes in the presence of isoguvacine (40 microM). However, the affinity of the drug for GABAB binding sites was significantly less than that of GABA (0.0005 potency ratio) and showed no apparent stereoselectivity. 6. These results indicate that while (-)-HA-966 appears to act as a direct GABAB receptor agonist in vitro, its affinity for this receptor site is substantially less than that of GABA or baclofen and unlikely to account for the depressant actions of this drug which occur at levels approximately ten fold lower in vivo.

Apamin-sensitive Ca(2+)-activated K+ channels regulate pacemaker activity in nigral dopamine neurons.

Mesencephalic dopamine-containing neurons exhibit a Ca(2+)-dependent oscillation in membrane potential believed to underlie the ability of these cells to maintain spontaneous activity in the absence of afferent synaptic drive. In the present series of experiments, sharp electrode intracellular recording techniques were used in conjunction with an in vitro brain slice preparation to explore the ionic mechanisms underlying rhythmogenesis in nigral dopamine neurons in the rat. Our results indicate that the K+ channel producing the prolonged post-spike afterhyperpolarization exhibited by these neurons is also principally responsible for generating the falling phase of the autogenous pacemaker oscillation. Alterations in the expression of this conductance are associated with marked changes in neuronal firing pattern, indicating that modulation of ligand-gated Ca(2+)-activated K+ channels may constitute a functional means of altering temporal coding among the major mesotelencephalic dopamine systems.

Effects of the enantiomers of (+/-)-HA-966 on dopamine neurons: an electrophysiological study of a chiral molecule.

The present study was conducted to evaluate the effects of the resolved enantiomers of (+/-)-1-1 hydroxy-3-aminopyrrolidone-2 ((+/-)-HA-966) on the electrophysiological properties of dopamine-containing neurons in the substantia nigra of the chloral hydrate anesthetized rat. Both (+)- and (-)-HA-966 produced a dose-dependent reduction in firing rate that eventually resulted in total cessation of spontaneous neuronal activity (ID50 = 5.7 and 57.8 mg/kg i.v., respectively). The inhibitory effects of both drugs were accompanied by a marked increase in the regularity of neuronal firing and a concomitant suppression of bursting activity. Although approximately 10-fold less potent than the (-) enantiomer, the inhibitory effects of (+)-HA-966 were completely antagonized by the centrally active, GABAB receptor antagonist, CGP-35348 (300 mg/kg i.v.). These data suggest that the complementary electrophysiological effects of the enantiomers of (+/-)-HA-966 on nigral dopamine neurons are mediated through a common mechanism of action possibly involving a novel interaction with GABAB receptors.

Effects of NPC16377, a potent and selective sigma receptor ligand, on the activity of mesencephalic dopamine-containing neurons in the rat.

NPC16377 is a highly selective sigma receptor ligand with low affinity for other neurotransmitter receptors. Preclinical studies indicate that the drug exhibits a pharmacological profile similar to that previously ascribed to atypical antipsychotic drugs. In the present series of experiments, extracellular recording techniques were used to assess the acute effects of NPC16377 on the electrophysiological properties of mesencephalic dopamine-containing neurons in the rat. Systemic administration of NPC16377 produced marginal increases in the firing rate of these neurons but failed to fully reverse the inhibitory effects of the dopamine agonists apomorphine and d-amphetamine. Low doses of the drug potentiated the rate-decreasing effects of d-amphetamine in the substantia nigra but not in the ventral tegmental area. Some of these effects are similar to the actions of atypical antipsychotic drugs, while others appear to be unique to this compound and may involve a direct interaction with sigma sites.

Excitatory amino acid-induced excitation of dopamine-containing neurons in the rat substantia nigra: modulation by kynurenic acid.

Kynurenic acid (KYNA), an endogenous antagonist of ionotropic excitatory amino acid (EAA) receptors, was tested for its ability to modulate N-methyl-D-aspartate (NMDA)- and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-induced excitation of dopamine (DA)-containing neurons in the zona compacta of the rat substantia nigra (SNc). Experiments were conducted using extracellular recording techniques in conjunction with an in vitro brain slice preparation. Bath application of NMDA (1-20 microM) or AMPA (0.5-10 microM) produced a concentration-dependent increase in the firing rate of SNc DA neurons but had no effect on firing pattern. The highest concentration of both agonists produced a rapid and reversible cessation of activity that was attributed to acute induction of depolarization block. Addition of glycine (GLY) (up to 100 microM) to the bathing solution had no effect on either basal firing rate or the increase in activity produced by NMDA. KYNA (10 microM-1 mM) antagonized the excitatory effects of both NMDA (15 microM) and AMPA (3 microM) in a concentration-dependent fashion (IC50:102 microM and 64 microM, respectively) without affecting basal firing rate. Perfusion of tissue slices with a modified Ringer's solution containing low Mg2+ (0.12 mM) increased NMDA-induced excitation but did not affect the antagonist properties of KYNA. D-serine (100 microM) reversed the ability of KYNA to block the excitatory effects of NMDA, suggesting that KYNA attenuates NMDA-induced excitation of SNc DA neurons via blockade of the GLY allosteric site on the NMDA receptor. The ability of KYNA to modulate the excitatory effects of both NMDA and non-NMDA agonists implies that endogenous KYNA may play a physiological role in regulating DA cell excitability.

(+-)-1-hydroxy-3-aminopyrrolidone-2 (HA-966) inhibits the activity of substantia nigra dopamine neurons through a non-N-methyl-D-aspartate receptor-mediated mechanism.

(+-)-1-hydroxy-3-aminopyrrolidone-2 [(+/-)-HA-966] is known to cause a rapid and selective increase in striatal dopamine (DA) levels--an effect that has been attributed to the compound's presumed ability to block the spontaneous electrical activity of nigrostriatal DA neurons. In the present series of experiments, extracellular single unit recording techniques were used to explore this premise in the chloral hydrate-anesthetized rat and to compare the pharmacological effects of the racemic form of HA-966 with its resolved enantiomers. Systemic administration of (+/-)-HA-966 produced a dose-dependent inhibition in the firing rate of DA neurons in the zona compacta of the substantia nigra. The highest dose tested (40 mg/kg i.v.) completely inhibited the spontaneous activity of all cells tested. Pretreatment with naloxone (5 or 10 mg/kg i.v.) reduced the initial rate of decline in firing rate and the duration of inhibition but did not prevent a single dose of 40 mg/kg of (+/-)-HA-966 from totally inhibiting DA cell impulse flow. Systemic administration of the (-)-enantiomer of HA-966 (30 mg/kg i.v.) inhibited neuronal activity in a manner analogous to a single injection of 40 mg/kg of (+/-)-HA-966. Comparable doses of the (+)-enantiomer failed to affect significantly the firing rate of substantia nigra DA neurons but suppressed bursting activity and "normalized" neuronal discharge pattern.(ABSTRACT TRUNCATED AT 250 WORDS)

On central muscle relaxants, strychnine-insensitive glycine receptors and two old drugs: zoxazolamine and HA-966.

Zoxazolamine is in the centrally-acting muscle relaxant class of drugs, which reportedly act by decreasing CNS interneuronal activity. These drugs, but not anxiolytics, decrease dopaminergic turnover and induce a pacemaker-like discharge pattern in dopaminergic neurons. A mechanism for these effects was not found in previous reports. We observed that (+)-HA-966, an inhibitor of the glycine modulatory site on the NMDA receptor, has a similar effect on dopaminergic impulse flow, which suggested that this may be the possible site of action of classical muscle relaxants. However, a competitive antagonist of NMDA receptors, NPC-12626, had little effect on impulse flow. Binding of 20 nM [3H]-glycine to cortical synaptosomal membranes was inhibited by (+)-HA-966, IC50 = 3.16 microM, but only poorly by zoxazolamine, IC50 V 474 microM, and chlorzoxazone, a related drug, caused no displacement. The drugs were then tested for protection from amphetamine neurotoxicity. Neither 50 mg/kg zoxazolamine nor 30 mg/kg (+)-HA-966 prevented (+)-amphetamine (0.1 mmol/kg plus 10 mg/kg iprindole) depletion of striatal dopamine (DA), but 3.0 mg/kg of MK-801, a non-competitive NMDA receptor antagonist, did protect DA content. Since baclofen induces a regular firing rate in DA neurons, zoxazolamine and (+)-HA-966 were tested for displacement of 10 nM [3H]-1-baclofen from cortical synaptosomal GABAb receptors, but were ineffective. Thus, the effects of these muscle relaxants on DA neurons are mediated by a mechanism other than strychnine-insensitive glycine or GABAb receptors.

Repetitive firing properties of putative dopamine-containing neurons in vitro: regulation by an apamin-sensitive Ca(2+)-activated K+ conductance.

Intracellular recording techniques were used to study the effects of apamin (APA), a selective inhibitor of one type of Ca(2+)-activated K+ channel, on the electroresponsive properties of dopamine (DA)-containing neurons within the zona compacta of the substantia nigra (SNc) in rat. Bath application of APA (1 microM) blocked the slow component of a complex post-spike afterhyperpolarization (AHPs) without affecting other characteristics of the action potential. Blockade of AHPs was accompanied by an increase in the number and frequency of action potentials evoked by depolarizing current pulses. However, APA failed to affect the cellular mechanisms underlying spike frequency adaptation or post-stimulus inhibitory period. These data indicate that AHPs can exert a strong influence on the interspike interval but is probably not involved in regulating slower adaptive neuronal responses.

The effects of pertussis toxin on autoreceptor-mediated inhibition of dopamine synthesis in the rat striatum.

Activation of synthesis-modulating dopamine autoreceptors by dopamine or its agonists has been shown to inhibit dopamine synthesis in the rat striatum. However, systemic administration of the direct-acting dopamine agonist apomorphine failed to inhibit dopamine synthesis in striata from rats that had received local unilateral administration of pertussis toxin. Apomorphine did reduce dopamine synthesis by greater than 50% in sham injected control rats as well as in the striata opposite to the side of pertussis toxin injection. Examination of G proteins in striatal tissue revealed that 61% of the G proteins were ADP-ribosylated in vivo by direct pertussis toxin injection. These data suggest that guanine nucleotide regulatory proteins mediate the effects of activation of striatal synthesis-modulating dopamine autoreceptors.