Molecular biology of glycinergic neurotransmission

Glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem of vertebrates. Glycine is accumulated into synaptic vesicles by a proton-coupled transport system and released to the synaptic cleft after depolarization of the presynaptic terminal. The inhibitory action of glycine is mediated by pentameric glycine receptors (GlyR) that belong to the ligand-gated ion channel superfamily. The synaptic action of glycine is terminated by two sodium- and chloride-coupled transporters, GLYT1 and GLYT2, located in the glial plasma membrane and in the presynaptic terminals, respectively. Dysfunction of inhibitory glycinergic neurotransmission is associated with several forms of inherited mammalian myoclonus. In addition, glycine could participate in excitatory neurotransmission by modulating the activity of the NMDA subtype of glutamate receptor. In this article, we discuss recent progress in our understanding of the molecular mechanisms that underlie the physiology and pathology of glycinergic neurotransmission.     

Effects of subchronic administration of metrifonate on cholinergic neurotransmission in rats

The effects of subchronic oral administration of metrifonate, a long-acting cholinesterase (ChE) inhibitor, on cholinergic neurotransmission were assessed in young adult male Wistar rats. Animals were treated twice daily with metrifonate. In a pilot study testing a 100 mg/kg dose of metrifonate for up to 14 days, ChE activity was found to steadily decrease to reach maximum inhibition levels of about 55%, 80% and 35% in brain, erythrocytes and plasma. Steady-state inhibition levels were attained by the 10th day of treatment. When metrifonate-treatment was discontinued, ChE activity in plasma returned to control levels within another day, while erythrocyte and brain ChE activity took more than 2 weeks to recover. In subsequent dose-response studies, metrifonate treatment was given for 3 and 4.5 weeks at doses of 0, 12.5, 25, 50, and 100 mg/kg, to different groups of animals, respectively. Correlation analysis indicted that brain ChE inhibition was more accurately reflected by erythrocyte than by plasma ChE inhibition, although all effects were highly correlated. The changes in ChE activity were not paralleled by changes in other parameters of the cholinergic neurotransmission, such as acetylcholine synthesis rate or acetylcholine receptor binding. It is therefore concluded that repeated administration of metrifonate to rats induces a long-lasting inhibition of ChE activity in a dose-related and predictable manner, which is neither subject to desensitization nor paralleled by counterregulatory downregulation of muscarinic or nicotinic receptor binding sites in brain.     

Effect of L-glutamate on cholinergic neurotransmission in various brain regions and during the development of rats, when administered perinatally

Glutamate, as a monosodium salt (MSG) has neurotoxic effects on some brain regions when systemically given to young rats. Few studies have been conducted to establish the mechanisms involved in studying neurotoxicity resulting in neuronal death by glutamate (Glu) and its effects as related to different brain neuropathologies under in-vivo conditions and where the cholinergic system shows vulnerability. Thus, this paper aims to evaluate the binding kinetics of quinuclynidyl benzylate (QNB) to muscarinic receptors for acetylcholine and the activity of choline acetyltransferase (CAT) in rats treated with MSG (4 mg/g on days 1, 3, 5, and 7 after birth) during the rat development stages (days 14, 21, 30, and 60) in different brain regions. The results show that perinatal treatment with MSG significantly decreases the CAT activity and increases the affinity of [3H]-QNB and the number of receptors of the brain cortex during the ages studied. The striatum showed increased CAT activity and BMAX on days 30 and 60 after birth. Affinity and the number of receptors increased in the hippocampus only between days 21 through 60 after birth. NaCl given at MSG equimolar doses only modified the CAT activity but had no effect on the [3H]-QNB binding kinetics in any of the regions studied. The results show that MSG alters cholinergic neurotransmission in the central nervous system (CNS) and induces the development of compensating events suggesting an involvement in neuronal plasticity during the development of rat CNS.     

Regulation of uveal sympathetic neurotransmission by peroxides

PURPOSE: To investigate the effect of naturally occurring and synthetic peroxides on norepinephrine release from isolated iris-ciliary bodies of several mammalian species. METHODS: Hemiirides (bovine) and iris-ciliary bodies (human, rabbit, and rat) were incubated in Krebs solution containing [3H]-norepinephrine ([3H]NE) for 60 minutes. After incubation, tissues were set up for studies of [3H]NE release using the superfusion method. Release of [3H]NE was elicited through electrical field stimulation. RESULTS: In bovine irides, hydrogen peroxide (H2O2), cumene hydroperoxide (cuOOH), and tert-butyl hydroperoxide (buOOH) caused a concentration-dependent potentiation of field-stimulated [3H]NE release with the following rank order of potency: cuOOH > H2O2 > buOOH. Furthermore, the free radical scavenger, melatonin (2 mM), prevented the enhancement of evoked [3H]NE overflow elicited by H2O2 and cuOOH. At equimolar concentrations, H2O2 (1 mM) increased stimulated [3H]NE release from rabbit, human (mean age, 29.7; range, 15 to 48 years), and Fischer 344 rat (4 months old) iris-ciliary bodies by 98%, 50%, and 40%, respectively. However, H2O2 (1 mM) caused a 9% increase in evoked [3H]NE release in tissue from aged Fischer 344 rats (30 months old) and a 5% decrease in neurotransmitter release in tissue from old human donors (mean age, 72.3 years; range, 69 to 74 years). CONCLUSIONS: Peroxides such as H2O2 can potentiate sympathetic neurotransmission in the anterior uvea of several mammalian species. In bovine irides, H2O2-induced enhancement of neurotransmitter release can be mimicked by synthetic peroxides and may involve the generation of reactive oxygen species.     

Effects of 5-day hypoxia on cardiac adrenergic neurotransmission in rats

Chronic hypoxia induces an overall sympathetic hyperactivation associated with a myocardial beta-receptor desensitization. The mechanisms involved in this desensitization were evaluated in 32 male Wistar rats kept in a hypobaric pressure chamber (PO2 = 40 Torr, atmospheric pressure = 450 Torr) for 5 days. In hypoxic compared with normoxic conditions, plasma norepinephrine (NE) levels were higher (2.1 +/- 0.7 vs. 0.6 +/- 0.2 ng/ml) with no difference in the plasma epinephrine levels (2.2 +/- 0.7 vs. 1.8 +/- 0.3 ng/ml). In hypoxia neuronal NE uptake measured by [3H]NE was decreased by 32% in the right ventricle (RV) and by 35% in the left ventricle (LV), and [3H]mazindol in vitro binding showed a decrease in uptake-1 carrier protein density by 38% in the RV and by 41% in the LV. In vitro binding assays with [3H]CGP-12177 indicate beta-adrenoceptor density reduced by 40% in the RV and by 32% in the LV, and this was due to reduced beta1-subtype fraction (competition binding experiments with practolol). Hypoxia reduced the production of cAMP induced by isoproterenol (36% decrease in the RV and 41% decrease in the LV), 5'-guanylylimododiphosphate (40% decrease in the RV and 42% decrease in the LV), and forskolin (39% decrease in the RV and 41% decrease in the LV) but did not alter the effect of MnCl2 and NaF. Quantitation of inhibitory G-protein alpha-subunit by immunochemical analysis showed a 46% increase in the cardiac-specific isoform Gialpha2 in hypoxic hearts. The present data demonstrate that in rats 5-day hypoxia leads to changes in pre- and postsynaptic myocardial adrenergic function. The myocardial desensitization associated with both a reduction in externalized beta1-adrenoceptor and an increase in inhibitory G-protein subunit may be caused by increased synaptic NE levels due to impaired uptake-1 system.     

Amino acids in neurotransmission and disease

BACKGROUND: The amino acids, glutamate, GABA and glycine are involved in normal cellular function as well as in neuro-transmission. Glutamate in particular may be linked to neuron development and an oversupply may be the major cause of many acute and chronic neurological diseases. Such diseases include retinopathy of prematurity, glaucoma, hypertension, diabetes and ischemic damage secondary to vessel occlusion. CONCLUSIONS: This paper provides a review of the localization, proposed function and the mechanisms of manufacture and deactivation of the amino acid neurotransmitters. Current mechanisms of excitotoxicity are also discussed. In addition, the data presented from an animal model of retinal ischemia show morphological and neurochemical changes consistent with glutamate induced neurotoxicity.     

Composite autonomic scoring scale for laboratory quantification of generalized autonomic failure

An autonomic reflex screen, which consisted of a quantitative sudomotor axon reflex test, orthostatic blood pressure and heart rate response to tilt, heart rate response to deep breathing, the Valsalva ratio, and beat-to-beat blood pressure measurements during phases II and IV of the Valsalva maneuver, tilt, and deep breathing, was used to develop a 10-point composite autonomic scoring scale of autonomic function. The scheme allots 4 points for adrenergic and 3 points each for sudomotor and cardiovagal failure. Each score is normalized for the compounding effects of age and sex. Patients with a score of 3 or less on the composite autonomic scoring scale have only mild autonomic failure, those with scores of 7 to 10 have severe failure, and those with scores between these two ranges have moderate autonomic failure. The sensitivity and specificity of the method were assessed by evaluating the composite autonomic scoring scale in four groups of patients with known degrees of autonomic failure: 18 with multisystem atrophy, 20 with autonomic neuropathy, 20 with Parkinson's disease, and 20 with peripheral neuropathy but no autonomic symptoms. The composite scores (means +/- SD) for these four groups, respectively, were as follows: 8.5 +/- 1.3, 8.6 +/- 1.2, 1.5 +/- 1.1, and 1.7 +/- 1.3. Patients with symptomatic autonomic failure had scores of 5 or more, those without symptomatic autonomic failure had scores of 4 or less, and no overlap existed in these groups. Thus, autonomic laboratory tests should be useful in grading the degree of autonomic failure.     

Influence of autonomic tone on QT interval duration

The autonomic tone has been shown to influence the duration of the QT interval, however the independent contribution of sympathetic and parasympathetic tone is not fully elucidated. The influence of autonomic tone on QT duration was studied in 10 young healthy volunteers by evaluating the changes in QT and RR duration induced by i.v. isoproterenol infusion and by standing before and after i.v. administration of propranolol or atropine. Furthermore, the relationship between RR interval and QT duration was evaluated during nocturnal sinus arrhythmia and submaximal exercise test. Low doses of isoproterenol reduced RR (p < 0.01) but not QT interval duration, while higher doses influenced both RR (p < 0.0001) and QT (p < 0.001) duration. Propranolol did not influence standing-induced shortening of RR and QT intervals; on the contrary, atropine administration abolished standing-induced QT interval shortening, without influencing RR changes. QT duration resulted significantly related to preceding RR interval at peak exercise (r = 0.87, p < 0.001) and during nocturnal sinus arrhythmia (r = 0.73, p < 0.0005), however, the regression lines showing the correlation between QT and preceding RR interval were different. Both sympathetic and parasympathetic tone appear to contribute to heart rate-independent changes in QT duration. In the basal state parasympathetic more than sympathetic tone influences the relation QT-heart rate. Major increases of sympathetic nervous system activity may change the relation QT-heart rate. Thus, in case of abrupt autonomic changes, any proposed formula for heart rate correction of QT may result inappropriate, also in the normal range of heart rate.     

Effect of high intensity drive train stimulation on dispersion of atrial refractoriness: role of autonomic nervous system

OBJECTIVES: This study evaluated the effect of high intensity drive train (S1) stimulation on the atrial effective refractory period (ERP) and its relation to the autonomic nervous system. BACKGROUND: High intensity S1 stimulation was demonstrated to shorten the ventricular ERP and to increase dispersion of refractoriness. These effects may be due to local release of neurotransmitters. The response of the atrium and ventricle to neurotransmitters was different. The effects of high intensity S1 stimulation at the atrial tissue were evaluated. METHODS: Forty patients without structural heart disease were studied. In group 1, 20 patients, the atrial ERP was measured at 0, 7, 14, 21 and 28 mm away from the S1 site under both twice diastolic threshold and high intensity (10 mA) S1 stimulation. The same protocol was repeated after sequential administration of propranolol (0.2 mg/kg body weight) and atropine (0.04 mg/kg). In group 2, the other 20 patients, the atrial ERP was studied at three atrial sites (high lateral right atrium [HLRA], right posterior interatrial septum [RPS] and distal coronary sinus [DCS] with twice diastolic threshold and high intensity S1 stimulation at baseline and after sequential autonomic blockade. The three atrial sites were randomly assigned as the S1 location. RESULTS: In group 1, high intensity S1 stimulation shortened the atrial effective refractory period most prominently at the site of S1: (mean +/- SD) 13.3 +/- 6.4% (p < 0.001), 8.1 +/- 3.8% (p < 0.001), 4.8 +/- 4.3% (p < 0.001), 3.7 +/- 4.7% (p < 0.001) and 0.5 +/- 2.6% at 0, 7, 14, 21 and 28 mm from the S1 site, respectively. The effect of high intensity S1 stimulation was blunted with propranolol and autonomic blockade but persisted after atropine alone. High intensity S1 stimulation also increased dispersion of refractoriness (from 23 +/- 11 ms to 31 +/- 12 ms, p = 0.01), which was eliminated with autonomic blockade. In group 2, high intensity S1 stimulation had similar effects at different locations (ERP shortening of 10.8 +/- 2.7%, 10.8 +/- 2.2% and 12.2 +/- 4.6% at the HLRA, RPS and DCS, respectively). The responses to sequential autonomic blockade were similar to those in group 1. However, high intensity S1 stimulation at HLRA increased dispersion of refractoriness, but at DCS it reduced dispersion of refractoriness. CONCLUSIONS: High intensity S1 stimulation led to local shortening of the atrial ERP and increased dispersion of refractoriness. These effects were blunted with propranolol and autonomic blockade. High intensity S1 stimulation at the HLRA increased dispersion of atrial refractoriness, whereas the same stimulation at the DCS decreased dispersion of atrial refractoriness.     

Insect neurotransmission: neurotransmitters and their receptors

The roles of acetylcholine, dopamine, octopamine, tyramine, 5-hydroxytryptamine, histamine, glutamate, 4-aminobutanoic acid (gamma-aminobutyric acid) and a range of peptides as insect neurotransmitters are evaluated in terms of the criteria used to identify transmitters. Of the biogenic amines considered, there is good evidence that acetylcholine, dopamine, octopamine, 5-hydroxytryptamine, and histamine should be considered to be neurotransmitters, but the case for tyramine is less convincing at the moment. The evidence supporting neurotransmitter roles for glutamate and gamma-aminobutyric acid at specific insect synapses is overwhelming, but much work remains to be undertaken before the full significance of these molecules in the insect nervous system is appreciated. Attempts to characterise biogenic amine and amino acid receptors using pharmacological and molecular biological techniques have revealed considerable differences between mammalian and insect receptors. The number of insect neuropeptides isolated and identified has increased spectacularly in recent years, but genuine physiological or biochemical functions can be assigned to very few of these molecules. Of these, only proctolin fulfills the criteria expected of a neurotransmitter, and the recent discovery of proctolin receptor antagonists should enable the biology of this pentapeptide to be explored fully.     

Effects of noise on some autonomic system activities

Experiments were conducted on the effects of various expected noise conditions upon autonomic system activity in men during rest and work (bicycle ergometer). Skin temperature and heart rate were not appreciably, if at all, affected by any of the noises. Wide-band, predominantly low-frequency noise, at a level of 92 dB, A-weighted, generally caused a decrease in pulse amplitude (indicative of constriction of peripheral blood vessels) during either work or rest, whereas an equally intense one-third octave band of random noise, center frequency of 3150 Hz, had no appreciable effect on pulse amplitude. Repeated exposures to the wide-band noise showed some adaptation or habituation of the pulse amplitude response during conditions of either work or rest. The results were the same for fast rise time (impulsive) bursts of wide-band noise as for bursts with slow, gradual onsets. Rapid interruptions of wide-band noise caused less of a decrease in average pulse amplitude than did uninterrupted noise. It is suggested that constriction of peripheral blood vessels in response to expected intense low-frequency or wide-band noises is more related to auditory, reflexive protective mechanisms than to autonomic system responses generally considered to be stressful to the organism.     

Nitric oxide and the non-adrenergic non-cholinergic neurotransmission

In the early 1960s, the first evidence was reported demonstrating neurally mediated responses in the presence of adrenergic and cholinergic antagonists, leading to the introduction of the concept of non-adrenergic non-cholinergic neurotransmission. The inhibitory component of this part of the autonomic nervous system has been illustrated in numerous organ systems mediating a wide range of physiological events. Since the discovery of these nerves, several substances have been proposed as putative neurotransmitter, with ATP and vasoactive intestinal polypeptide as main candidates. Finally, the ongoing research on the nature of the substance released by these nerves has generated the nitrergic theory proposing nitric oxide as putative neurotransmitter. By now, increasing evidence is reported to support the idea that inhibitory neurons release more neurotransmitters, interacting with each other at pre- and/or postsynaptic levels.     

Metformin inhibits ganglionic neurotransmission in renal nerves

Intravenous administration of the antihyperglycemic agent metformin decreases arterial pressure and sympathetic nerve activity (SNA). To test the hypothesis that metformin inhibits SNA by interrupting ganglionic neurotransmission, we compared the actions of intravenous administration of metformin and the ganglionic blocker trimethaphan on postganglionic renal and preganglionic adrenal sympathetic nerves in pentobarbital-anesthetized male Sprague-Dawley rats. Intravenous metformin elicited dose-dependent decreases in postganglionic renal SNA (1 mg/kg: 0 +/- 0%; 10 mg/kg: -20 +/- 4%; 100 mg/kg: -92 +/- 3%; n = 7). Conversely, only the maximal dose of metformin affected preganglionic adrenal SNA (100 mg/kg: delta adrenal SNA = -14 +/- 6%; n = 8). Ganglionic blockade with intravenous trimethaphan (5 mg/kg) produced a differential sympathoinhibitory response similar to the response observed after high-dose metformin (delta renal SNA = -100 +/- 3%; delta adrenal SNA = -17 +/- 7%; P < .001). Preganglionic renal neurons were electrically stimulated in the spinal cord, before and during the peak of the sympathoinhibitory response to intravenous metformin, and the magnitude of the stimulus-evoked increases in postganglionic renal SNA were compared. Metformin dose-dependently attenuated the magnitude of the increase in postganglionic renal SNA elicited by stimulation of the spinal cord (30 mg/kg: -23 +/- 8%; 90 mg/kg: -65 +/- 11%; 270 mg/kg: -91 +/- 8%; n = 6 per dose). We conclude that high-dose intravenous metformin interrupts ganglionic neurotransmission in renal nerves.     

Electrophysiological tests of autonomic function in patients with idiopathic autonomic failure syndromes

Three electrophysiological tests of autonomic function were performed in patients with autonomic nervous system dysfunction to define test sensitivities and specificities. The skin sympathetic response, Valsalva ratio, and heart rate variation with deep breathing were studied in 10 patients with multiple system atrophy (MSA) and in 7 patients with pure (also called progressive or primary) autonomic failure (PAF); control subjects were 17 normal individuals of similar age. Thirteen patients had abnormal skin sympathetic responses, and 16 had abnormal Valsalva ratios. Fourteen patients had an abnormal variation of the heart rate with deep breathing. Taking the three tests together, binary logistic regression for distinguishing between patients and normal subjects correctly classified 91% of the 33 individuals for whom there were complete data with sensitivity of 88% and specificity of 94%. However, only 69% of the patients could be correctly classified by a logistic regression for discriminating between MSA and PAF. Electromyography (EMG) studies showed that 7 of 8 patients with MSA but only 2 of 7 patients with PAF (both multiparous women) had denervation of the rectal sphincter muscle. The EMG study is, therefore, valuable in men, but has a high false positive rate in women, probably because of pudendal nerve injury from parturition.     

Recycling of L-citrulline to sustain nitric oxide-dependent enteric neurotransmission

Neurons that synthesize nitric oxide from arginine produce stoichiometric amounts of citrulline. We investigated whether nitric oxide-releasing enteric neurons have the capacity to recycle citrulline to arginine and thereby sustain nitrergic neurotransmission. Argininosuccinate synthetase-like immunoreactivity and argininosuccinate lyase-like immunoreactivity, enzymes capable of citrulline to arginine conversion, were both localized in discrete populations of myenteric and submucosal neurons in the canine proximal colon. Argininosuccinate synthetase-like immunoreactivity and argininosuccinate lyase-like immunoreactivity co-localized with neuronal beta-nicotinamide adenine dinucleotide phosphate diaphorase staining, a marker for nitric oxide synthase. The functional significance of argininosuccinate synthetase-like immunoreactivity and argininosuccinate lyase-like immunoreactivity was shown by testing the effects of exogenous citrulline on responses to enteric inhibitory nerve stimulation, which were assessed by measuring contractions, inhibitory junction potentials and electrical slow waves. As shown previously, arginine analogues (L-nitroarginine methyl ester or L-nitroarginine; 100 microM) inhibited nitric oxide-dependent responses, and excess L-arginine restored inhibitory responses. Citrulline alone (0.1-2 mM) had no effect on nitrergic transmission under control conditions, but in the presence of L-nitroarginine methyl ester or L-nitroarginine, citrulline (0.1-2 mM) restored nitrergic transmission in a concentration-dependent manner. Other neutral amino acids (L-serine, L-leucine) did not mimic the effects of citrulline. Taken together, these data suggest that enteric nitrergic neurons have the enzymatic apparatus and functional capability of recycling citrulline to arginine.     

Glutamatergic neurotransmission involves structural and clinical deficits of schizophrenia

BACKGROUND: Phencyclidine and ketamine induce a syndrome closely resembling schizophrenia due to their blockade of N-methyl-D-aspartate (NMDA) receptor. These findings suggested that some aspects of schizophrenia are associated with decreased NMDA--glutamatergic function. We hypothesized that structural and symptomatic deficits in schizophrenia are related to glutamatergic neurotransmission. METHODS: We studied the relationships among cerebrospinal fluid (CSF) glutamatergic markers, clinical presentation of schizophrenia, and CT parameters of brain structure in drug-free schizophrenics. RESULTS: We found no significant differences between patients with schizophrenia and controls in CSF glutamatergic markers. When patients with schizophrenia were considered as a group, significant negative correlations between glutamatergic markers and brain structural measures as well as clinical measures were observed. Cluster analysis reveals a group of lower indices of glutamatergic neurotransmission, and more prominent thought disorder as well as ventricular enlargement, and a group with increased glutamate level. CONCLUSIONS: The findings support the hypothesis that altered glutamatergic neurotransmission plays a role in the brain structure and the clinical symptoms of schizophrenia.     

Role of adenosine in noradrenergic neurotransmission during hemorrhagic hypotension

Glucagon-like peptide-1-(7-36) amide (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are known incretin hormones, released from enteroendocrine cells in response to food, that enhance insulin secretion, but only in the presence of elevated blood glucose. We used a rat insulinoma cell line, RIN 1046-38, to study the mechanisms underlying the interaction of incretins and glucose. We measured insulin secretion using RIA and the reverse hemolytic plaque assay. GLP-1 stimulates insulin secretion, with a half-maximal concentration of 34 pM. GLP-1 is approximately 2 orders of magnitude more potent than GIP. GLP-1 and GIP have additive effects at submaximal concentrations, but probably not at maximal concentrations, suggesting a common signal transduction pathway. The glucose requirement for GLP-1 action can be replaced by cell membrane depolarization (20 mM KCl in the extracellular medium), suggesting that a rise of intracellular Ca2+ may be an early step required for GLP-1 action. GLP-1 stimulates insulin secretion by significantly increasing the maximum rate of insulin secretion from 10.3 +/- 2.25 to 25.2 +/- 2.94 ng insulin/mg protein.h. GLP-1 acts by recruiting 1.5-fold more cells to secrete insulin as well as enhancing insulin secretion by individual cells. Combinations of stimuli, such as glucose, cell membrane depolarization, and GLP-1, can recruit 90% of RIN 1046-38 cells to secrete insulin.     

Surgical aspects of autonomic dysreflexia

Autonomic dysreflexia (AD) is a characteristic syndrome that occurs in spinal cord injury (SCI) patients with lesions above the sympathetic outflow at T6 and rarely in those with lesions below T10. Symptoms are initiated by noxious stimuli below the level of injury which result in massive sympathetic discharges from the isolated cord. These produce what may be called a sympathetic storm manifest by severe life threatening hypertension. Anesthesiologists and surgeons dealing with SCI patients must know how to recognize this syndrome, how to prevent its occurrence and how to manage it aggressively. Choice of anesthesia is frequently difficult and, in particular, it may be difficult to decide which type of anesthesia is best for patients susceptible to the syndrome. Therefore, we have conducted a retrospective study of SCI patients in the Department of Veterans Affairs Medical Center, Long Beach, California, where the Spinal Cord Injury Service is one of the largest in the country.     

DARPP-32: regulator of the efficacy of dopaminergic neurotransmission

Dopaminergic neurons exert a major modulatory effect on the forebrain. Dopamine and adenosine 3',5'-monophosphate-regulated phosphoprotein (32 kilodaltons) (DARPP-32), which is enriched in all neurons that receive a dopaminergic input, is converted in response to dopamine into a potent protein phosphatase inhibitor. Mice generated to contain a targeted disruption of the DARPP-32 gene showed profound deficits in their molecular, electrophysiological, and behavioral responses to dopamine, drugs of abuse, and antipsychotic medication. The results show that DARPP-32 plays a central role in regulating the efficacy of dopaminergic neurotransmission.