S-13-1 Dopamine D1 receptor activation decreases GABA release through adenosine A1 receptor after chronic cocaine treatment

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Fun~nonal role qf somatodendrtttc dopamine release in D1 -mediated signalling: basic and clinical aspects

S-13 Functional role of somatodendritic dopamine release in D~-mediated signalling: basic and clinical aspects Dopamine D1 receptor activation decreases GABA release through adenosine A1 receptor after chronic cocaine treatment John T Williams, Antonello Bonci Vb//um Institute for Advanced

Biomedical Research, Oregon Health Science Umversl~ Portland, Oregon 97201, USA The aim of this study was to mves:lgate the dopamlne D1 mediated r;-odulat on of the GABA B IPSP in ventral tegmental area of guinea peg before arid after chronic cocaine treatment -erm~nals originating from nucleus accum b e n s w e r e s t ~ m u l a t e d e l e c t r i c a l l y ( 5 0 0 # s 70Hz, 10pulses)toreleaseGABA acting on postsynapt~c GABA B receptor The GABA B IPSP was isolated pnarmacologically by applying 2-amino-5-phosphonopentanoic acid (AP 5). 6-cyano 2,3-dihycroxy 7-nitro-quinoxaline (CNQX), picrotoxm and stnchnine Our results show that D1 receptor activation produces a decrease in GABA release in animals sacrifleo one week afte" the last cocaine in ec*,ior'. wnereas in untreated controls we observed a D1 mediated increase n GABA release, as previously reported The effect of forskolin, an adenylyl cyclase activator, was similarly opposite ~n the two groups of adrenals It has been shown that increased extracellular levels of adenosine can result from cAMP metabolism, t is also known that presynapt~c A1 adenosine receptor activation inhibits GABA release in VTA, so we hypothesized tnat D1 or forskolin mediated decrease of GABA B IPSP occur indirectly through A1 a d e n o s l n e r e c e p t o r a c t w a t i o n The tnhibition of GABA release caused ov D1 receptor activation or by forskoiin was reversed by an adenosme antago nist, 8 CPT. and by drugs able to decrease the extracellular adenosine levels such as RO-2O 1724, probenecid and adenosine deaminase. These results suggest that one week after chronic cocame treatment the Dl-adeqyly[ cyc:ase system is upregulated, eading to a large increase ~n extraeelu=ar adenosine. Tnis supports the r'yoothesis that chronic cocaine profoune!y alters the D1/adenosme oalance in the ventral tegmental area and that th~s interaction cou;d play a crucial role in sensitization to psychostlmuiants

References Cameron DL and W~lliams J T (19933 Do;,amlne D1 receptors facditate trarsm~tr,~r re lease Nature 366, 344 347

Somatodendritic dopamine stimulates glutamate and GABA release via D1 receptors RW Kalivas, X~Y L u Alcohol and Drug Abuse Program, ;'l/ash/ngton ~',*ate Umvers/~ Pullman, WA Somatodendntlc release of cooam~ne ~n the ventral tegmental area ~VTA! acts upon D 2 recepto's located on the cell surface to hyperpolanze dopamlne neurons This automhrbiterymechanlsm is cntical for the homeostatlc maintenance of dopam;ne cel firing patterns In addlt~or" to try{! direct inhibitory feedback by somatodendrdic dopamme onto D 2 ~eceprora, dopamlne can also simulate D1 receptors located on GABAergic afferen! tem~inals to dopamine cells D 1 receptor stimulation promotes GABA re lease which cad also hvperpolanze dopamiqe cells v~a activating GA:~AB receptors. In addition to mh:bltory feedback, stimulation of D1 receptors can increase the extracellular content of glutamate This poses tne posal bility that in addition to negative feedback, stimulation of D 1 receptors by somatodendritlc dopamme can promote positive feedback onto c~opamlr'e cells via indirectly stimulating excitatory amino acid receptors While D1 receptors in the substantla nlgra have been shown to be located on GABAergic striaton,gral afferents, in the adjacent VTA the density or D~ receptors is substantJallyless and the location of [)1 receptors has :t'erefo'e been difficult toascertaln However, tt appears than neurons w i t h n t h ~ V - ~ , de not exhibit mRNA ~or D 1 recepto's posing tne likelihood that, as ~' the substantia nigra the receptors will be Iocahzed to oresynaptlc terminai~ -o evaluate this oosslb~hty, neurons projecting to the VTA were rettog~adelv labeled by iontophoret~c deposits of Fluoro-Gold made ~nto the VTA Com~al t~ssue sections were made from regions containing retrogradelv abe!led, cells, and the sections were double !abeled for mRNA of D 1 receptors ~ ,~g in sltu hybqdization Approximately 20'% of the retrogradely labeled ce s were deuble-laeeled for D* mRNA in the shell of the nucleus a c c d m o e ' s and prefrontal cortex The projections from the nucleus accumbeFa and prefrontal cortex to the VTA utiltze GABA and glutamate, respechveN ~ neurot'ansmitters

These anatomical data support the neurochemical findings that both r~egative and positive feedback onto dopamine cells in the VTA may arise from somatodendritic dopamine stimulation of D1 receptors on GABAergic and glutamaterglc terminals, respectively

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Functional role of somatodendritic dopamine release in basal ganglia circuitry

Elizabeth D Abercrombie. Wia Timmerman, Peter DeBoer. Centerfor Molecular 8 Behavioral Neuroscience, Rutgers Universi84 Newark, NJ 07102, USA Studies of somatodendritic dopamine (DA) release in substantia nigra (SN) pnmarily focus on D-2 autoreceptor regulation of dopaminergic neuronal activity We present electrophysiological and neurochemical evidence that somatodendritic DA release also can act, via D-1 receptors located on striatonigral terminals in SN pars reticulata (SNpr). to influence thalamocortical actwity such that glutamatergic input to striatum is increased. Behavioral experiments indicate that the influence of somatodendritic DA release upon the basal ganglia circuitry contributes to the expression of DA-mediated be haviors It is proposed that DA can have significant, and possibly opposing, actions in governing basal ganglia function by acting post-synoptically at both the nerve terminal level in striatum and at the somatodendritic level in SN Somatodendntlc DA and Thalarnocort~ca/ Regulation. Intranigral infusion of ampnetemlne (AMPH - - 10 # g / 0 5 /zl; 5 min) produced a robust inhibition of multiple unit activity recorded from the GABAergic $Npr neurons in anesthetized rats Co-infusion of the D-1 receptor antagonistSCH-23390 ( 0 5 /~g) blocked the AMPH-induced decrease in SNpr activity. Co-infusion of the D-2 antagonist eticlopride (1 /~g) did not alter the effect of AMPH on th~s variable. Cortical EEG acquired during the SNpr infusions/recordings revealed a desynchrdnization in response to nigral AMPH infusion that could be prevented by co-infusion of SCH-23390 but not eticlopride. In parallel behaworal studies, identical infusions of AMPH into SNpr of awake rats consistentiy produced an mcrease in locomotor activity. This behavioral act,vat,on was blocked by co infusion of SCH-23390 It is hypothesized that increased inhibition of SNpr outputs, ~n particular the nigrothalamic project on, ~s elicited by stimulation of SNpr D-1 receptors resulting in disinhibition of thalamocortical activity and of behavioral output. Sornatodendntic DA and Stnatat Excitation. In microdialysis studies in awake rats, systemic AMPH administration (2-10 mg/kg, i,p.) produced dose-dependent increases in extracellular DA levels both in striatum and ~q SNpr but elicited either no change or a decrease in striatal acetylcholine (ACh) o u t p u t Whereas local AMPH perfusion (10 and 100 iLM)into striatum consistently decreased striatal ACh output, perfusion of AMPH into SNpr (100/~M) produced a significant increase in this variable. This latter effect ~s not mediated via the nigrostriatal DA pathway since intranigral perfusion of AMPH attenuated the inhibition of ACh efflux produced by systemic administration of the D-2 agonist quinpirole (3 mg/kg). Intrastriatal perfusion of the glutamatergic antagonists kynurenic acid (100/zM}, CNQX (10 #M), and APV (100 /~M) decreased basal output of striatal ACh. Furthermore, the glutamatergic antagonists "unmasked" an inhibitory effect of systemic AM PH on striatal ACh effluxwith the following rank order of potency: CNQX > Kynurenic acid >> APM These data suggest that striatal DA release directly exerts D-2 receptor mediated inhibition of ACh whereas somatodendritic DA release indirectly leads to glutamatergic stimulation of striatal ACh output. The latter effect is presumed to occur via nigral D-1 receptor activation, inhibition of n~grofugal pathways, and subsequent increases in the activity of excitatory cortical and/or thalamic ~nputs to stnatum. In this example. therefore, the ultimate actions of nerve terminal release of DA and of somatodendritic DA release appear to oppose one another.

Involvement of the nigral Dt receptor in neuroleptic-induced oral dyskinesias in rats: clinical implications Carol A Tamminga, Maryland Psychiatric Research Center, Department of Paych/at04, University of Maryland, Ba/tt}-nore, Maryland 21228 Chronic neuroleptic administration is associated with tardive dyskinesia (T')} m -'umans and oral dyskinesias(VCMs) in rat These two involuntary movement syndromes in humans and rats share some phenomenologic and pharmacologic characteristics, thus VCMs in rats have been used as a "rnodeF' of TD in humans. An important feature of rat VCMs is that not all haloperidol-treated animals develop VCMs; therefore, correlates of chronic neurolept~c administration can be assessed separately from correlates of