Family 1 G protein-coupled receptor function in the CNS

Brain Research Reviews 41 (2003) 125–152 www.elsevier.com / locate / brainresrev

Review

Family 1 G protein-coupled receptor function in the CNS Insights from gene knockout mice Joanna M. Karasinska a , Susan R. George a,b , Brian F. O’Dowd a,b , * a

Department of Pharmacology, University of Toronto, Medical Sciences Building, 1 King’ s College Circle, Room 4353, Toronto, Ontario M5 S 1 A8, Canada b Centre for Addiction and Mental Health, Toronto, Ontario M5 S 2 S1, Canada Accepted 23 September 2002

Abstract Family 1 G protein-coupled receptors (GPCRs) are activated by a large number of ligands including photons, odorants, neurotransmitters and hormones and are involved in a wide variety of central and peripheral functions. Due to their wide distribution in the central nervous system (CNS), family 1 GPCRs play a major role in the regulation of neuronal activity and behaviour. In general, the lack of selective ligands for each member of the GPCR subfamilies has made it difficult to assign specific central functions to each receptor subtype. Advances in gene targeting techniques have allowed the inactivation of receptor genes in the mouse through homologous recombination leading to the generation of mouse ‘knockout’ models lacking one or more GPCRs. In this review, we have listed the family 1 GPCR knockout models produced in the past decade and we have summarized the findings obtained from studies on these mice with respect to CNS function.  2002 Elsevier Science B.V. All rights reserved. Theme: Neurotransmitters, modulators, transporters, and receptors Topic: Behavioural pharmacology Keywords: G protein-coupled receptor; Central nervous system; Gene knockout mice; Behaviour

Contents 1. Introduction ............................................................................................................................................................................................ 2. Changes in CNS function in mice lacking one or more family 1 GPCRs ...................................................................................................... 2.1. Adenosine receptors ........................................................................................................................................................................ 2.2. Adrenergic receptors ....................................................................................................................................................................... 2.3. Bombesin-like peptide receptors....................................................................................................................................................... 2.4. Cannabinoid receptors ..................................................................................................................................................................... 2.5. Dopamine receptors......................................................................................................................................................................... 2.6. Histamine receptors ......................................................................................................................................................................... 2.7. Muscarinic receptors ....................................................................................................................................................................... 2.8. Neurokinin receptors ....................................................................................................................................................................... 2.9. Neuropeptide Y receptors ................................................................................................................................................................. 2.10. Opioid receptors ............................................................................................................................................................................ 2.11. OFQ / N receptor............................................................................................................................................................................ 2.12. Serotonin receptors ........................................................................................................................................................................ 3. Advantages and limitations of GPCR gene knockout models ...................................................................................................................... 4. Conclusions ............................................................................................................................................................................................ References...................................................................................................................................................................................................

*Corresponding author. Tel.: 11-416-978-7579; fax: 11-416-978-2733. E-mail address: [email protected] (B.F. O’Dowd). 0165-0173 / 02 / $ – see front matter  2002 Elsevier Science B.V. All rights reserved. doi:10.1016/S0165-0173(02)00221-7

126 126 126 132 133 133 133 136 136 137 137 138 138 139 140 141 141

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1. Introduction The GPCR family can be subdivided into three major classes called receptor families 1, 2 and 3 [14]. Family 1 GPCRs, the largest of the three groups, are rhodopsin-like in their structure and are activated by a diverse range of ligands including photons and small molecules such as odorants, nucleotides and catecholamines as well as short peptides. Family 2 receptors are activated by large peptides and the ligands for family 3 GPCRs include glutamate, Ca 21 and g-aminobutyric acid (GABA). In addition, sequence-based receptor cloning techniques have identified over 100 novel family 1 receptors with yet unknown endogenous ligands called orphan GPCRs [172]. Family 1 GPCRs regulate a variety of physiological responses including neuronal, cardiovascular and endocrine functions. Many of the family 1 receptors are highly expressed in CNS and they are involved in regulation of behaviours ranging from motor control to learning and memory and brain reward. GPCR family 1 includes receptor subfamilies consisting of between one (apelin receptor) and as many as 13 members (serotonin receptors). The receptor subtypes in each subfamily share high sequence identity, common endogenous ligands and some similarities in receptor function. However, receptor subtypes differ in their affinity for ligands, expression levels, regions of distribution and second messenger coupling which allows each receptor to carry specialized functions. The traditional approach to assess GPCR function has involved strategies to activate or block function with pharmacological agents or antisense oligonucleotides. In addition, brain lesions and pharmacological manipulations have also been used to study GPCR-mediated central effects. The limitations of these techniques include the lack of ligands that are purely selective for each member of a receptor subfamily and the transient nature and inability of antisense oligonucleotides to cause complete gene silencing. In the past decade, advances in gene targeting techniques have allowed investigators to inactivate the gene encoding a protein of interest through homologous recombination in the mouse and to study the effects of the lack of this protein in vivo [33]. Briefly, a targeting vector carrying the mutated gene and selection markers is inserted into mouse embryonic stem (ES) cells. ES cells carrying the mutation are injected into blastocysts isolated from mice with a different coat color than the ES cell donors, which are then implanted into surrogate mothers. Chimeric animals identified based on coat colour are bred to a wild-type strain and offspring carrying the mutation are identified with genomic DNA analysis. Finally, mice heterozygous for the mutation are bred to obtain homozygous null mutant or ‘knockout’ mice. This technique has been used extensively, and hundreds of mouse gene knockout models with inactivated genes have been generated and characterized (see the mouse gene knockout database at http: / / research.bmn.com / mkmd). Gene target-

ing has been used successfully to inactivate and study GPCR function [272]. In fact, there are reports describing the generation of over 80 single, several double and one triple family 1 GPCR deletion models and these have been summarized in Table 1. Mice lacking the endogenous ligands for some GPCRs have also been generated (Table 2) and a comparison between Tables 1 and 2 demonstrates both similarities and differences between the phenotypes of mice lacking GPCRs or their endogenous ligands. The purpose of this review is to summarize the findings obtained from studies with mice deficient in one or more GPCRs caused by gene inactivation leading to the loss of receptor function through complete deletion or truncation. Specifically, we will concentrate on the effects of family 1 receptor gene inactivation on CNS function. Appropriate tests based on well-characterized rodent models have been described for behavioural analysis of mutant mouse strains including tests of general motor activity, reproductive function, learning and memory, feeding behaviour, nociception, aggression, anxiety, depression and brain reward [57,58]. Gene knockout mice have been used extensively to study mechanisms of behaviour [16,232,233,255]. The availability of rodent models has also greatly facilitated the use of knockout mice to study GPCR functions in behaviour. Studies on mice lacking one or more GPCRs have found that most of the mutants exhibited abnormalities in peripheral and central functions. Since a detailed summary of all the reported phenotypic changes of the mutant mice is beyond the scope of this review, Table 1 describes the findings reported in the initial studies performed on the receptor knockout mice. The rest of this review will focus on the effects of the deletion of one or more members of family 1 GPCRs on central function. In the following sections, we will attempt to summarize the findings obtained from neurochemical, electrophysiological and behavioural studies using GPCR gene knockout mice.

2. Changes in CNS function in mice lacking one or more family 1 GPCRs

2.1. Adenosine receptors The purine nucleoside adenosine has central functions that include depression of neurotransmission as well as regulation of sleep induction, analgesia and anxiety. The four known adenosine receptors A 1 , A 2A , A 2B and A 3 are widely distributed throughout the CNS and the periphery. In the brain, A 1 and A 2A receptors are expressed at higher levels than A 2B and A 3 receptors which are widespread in the periphery. The brain regions with high adenosine receptor distribution include the cerebral cortex, cerebellum, thalamus, striatum and hippocampus [89,106,257]. Two independent groups have recently reported the generation of A 1 receptor-deficient mice [134,314]. One

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127

Table 1 Family 1 GPCR gene knockout mouse models Receptor

Gene symbol

Genetic background

Phenotype

Reference

Adenosine A 1A

Adora1a

129OlaxC57BL

[134]

Adenosine A 2A

Adora2a

129SvxC57BL/6 N5 CD1

Adenosine A 3A Adenosine A 2A /dopamine D 2 Adrenergic a 1b Adrenergic a 2a

Adora3a

129SteelxC57BL/6, 129Steel 129OlaxC57BL/6

↓ adenosine inhibition of glutamatergic transmission, ↑ anxiety, ↓ intrathecal adenosine analgesia, ↓ post-hypoxia neuronal recovery Loss of tubuloglomerular feedback response to ↑ flow ↓ exploratory activity, ↑ anxiety, hypoalgesia, ↑ male aggressiveness, ↑ blood pressure and heart rate, ↑ platelet aggregation ↓ transient focal ischemia-induced brain injury

Adra1b Adra2a

129xC57BL/6 129xC57BL/6 129SvxFVB/N

[283] [41] [35] [189] [2]

Adrenergic a 2b Adrenergic a 2c Adrenergic a 2A /a 2C

Adra2b Adra2c

129SvJxC57BL/6 129SvJxFVB/N

Adrenergic b 1

Adrb1

Adrenergic b 2

Adrb2

129SvxC57BL/6x DBA2/J; 129Sv N5 FVB/N

Adrenergic b 3 Adrenergic b 1 /b 2

Adrb3

129SvJxxFVB/N

Angiotensin AT 1A

Agtr1a

129OlaxC57BL/6

Angiotensin AT 1B Angiotensin AT 2

Agtr1b Agtr2

129OlaxC57BL/6 129xC57BL/6 129SvJxFVB/N

Altered agonist inflammatory response Reversal of ↑ enkephalin in D 2 mutants ↓ blood pressure Loss of agonist hypotensive response ↑ sympathetic activity, ↓ cardiac tissue noradrenaline, down-regulation of cardiac b receptors Loss of agonist hypertensive response ↓ a 2 binding sites Lack of presynaptic control of noradrenaline release, ↑ plasma noradrenaline levels, cardiac hypertrophy, ↓ ventricular contractility High embryonic lethality, loss of agonist chronotropic and inotropic responses ↓ vasodilation response, ↑ total exercise capacity, exercise-induced hypertension, ↓ respiratory change ratio ↑ body fat, ↑ b 1 mRNA, loss of agonist effects ↓ agonist effect, ↑ b 3 agonist-induced effect, metabolic impairment Juxtoglomerular apparatus hypertrophy, ↓ blood pressure Loss of angiotensin response, ↓ systolic blood pressure No abnormal phenotype ↓ water deprivation-induced drinking response, ↓ locomotor activity, ↑ angiotensin vasopressor response ↑ blood pressure, ↓ locomotor activity, ↓ body temperature, ↑ angiotensin vasopressor response ↓ body weight, abnormal kidney structure, ↓ blood pressure Mild obesity, ↑ blood pressure, impairment of glucose metabolism, ↓ metabolic rate, ↑ food intake, ↑ plasma leptin levels ↑ locomotor activity, ↑ social responses Loss of bombesin suppression of glucose intake ↓ neuromedin B hypothermic effect Hypoalgesia, ↓ inflammatory response Loss of bradykinin action in smooth muscle and neurons Loss of central cannabinoid response, ↑ exploratory activity, ↓ morphine reward and withdrawal ↑ mortality rate, ↓ locomotor activity, ↑ ring catalepsy, hypoalgesia, some loss of central cannabinoid response Loss of cannabinoid immunomodulatory function Loss of mucosal host defence in the lung Lack of inguinal lymph nodes, impaired lymphocyte migration and intestinal Peyer’s patches development ↓ host defence, ↓ inflammatory response ↓ pancreatitis-induced pulmonary inflammation ↓ macrophage recruitment, ↑ eosinophils recruitment, ↓ host defence ↓ monocyte/macrophage recruitment, ↓ cytokine response Impaired macrophage function, ↑ T-cell cytokine production, ↑ immune response

129OlaxC57BL/6 Angiotensin AT 1A /A 1B Bombesin BRS-3

Brs3

129OlaxC57BL/6

Bombesin GRP-R

Grpr

Bombesin NMB-R Bradykinin B1 Bradykinin B 2 Cannabinoid CB 1

Nmbr Bdkrb1 Bdkrb2 Cnr1

N3 C57BL/6 129SvJxC57BL/6 129OlaxC57BL/6 129OlaxC57BL/6 129Sv/EvxC57BL/6 N6 CD1 129xC57BL/6

Cannabinoid CB 2 Chemoattractant C5a Chemokine BLR1 (CXCR5) Chemokine CCR1

Cnr2 C5ar Blr1

129xC57BL/6 129SvJxC57BL/6 129xCD1

Cmkbr1

Chemokine CCR2

Cmkbr2

129SvxC57BL/6 129/SvxC57BL/6 129/SvxICR 129SvxC57BL/6

Chemokine CCR5

Cmkbr5

129SvxICR

[314] [171]

[40]

[180] [181] [115]

[271] [45] [316] [270] [204] [132] [245] [116] [128] [245] [243]

[330] [110] [241] [252] [18] [170] [359] [28] [121] [87] [94] [97] [160] [17] [354]

J.M. Karasinska et al. / Brain Research Reviews 41 (2003) 125–152

128 Table 1. Continued Receptor

Gene symbol

Genetic background

Phenotype

Reference

Chemokine CCR6

Cmkbr6

129SvExC57BL/6

Impaired development of Peyer’s Patches, ↑ intestinal T cell levels, ↓ immune response Impaired development of Peyer’s Patches, ↑ intestinal T cell levels, ↓ inflammatory response Impaired T cell migration, abnormal lymphoid organs, ↓ immune response Impaired T helper type 2 cell responses, ↓ immune response ↑ spleen size, ↑ neutrophil levels Embryonic lethality due to hematopoietic and nervous system defects Loss of leukocyte adhesion to fractalkine, ↓ transplant rejection, ↓ natural killer cells levels in grafts Loss of cholecystokinin inhibition of food intake Atrophy of gastric mucosa, hypergastrinemia ↓ body weight, ↓ dynorphin expression, ↑ locomotor activity ↓ body weight, ↓ rearing behaviour, ↓ substance P expression Locomotor impairment, ↓ homozygous fertility, ↓ body weight, ↑ enkephalin expression, ↓ substance P expression, postural abnormalities ↑ enkephalin expression, ↑ plasma alpha-melanocyte stimulating hormone levels, ↑ proopiomelanocortin, ↓ locomotor activity, loss of autoreceptor function ↑ prolactin levels, pituitary lactotroph hyperplasia, Uterine adenomyosis ↑ enkephalin expression, ↓ locomotor activity, postural abnormalities, ↑ dopamine metabolite levels, ↑ D 3 levels ↑ D 2S expression, preservation of presynaptic D 2 function, loss of haloperidol catalepsy, D 1 signalling impairment ↑ D 2S expression, ↓ locomotion and rearing, loss of haloperidol catalepsy ↑ exploratory activity ↑ locomotor sensitivity to concurrent D 1 /D 2 activation, ↑ amphetamine reward sensitivity No gross abnormalities ↓ exploratory activity, ↑ locomotor effects of ethanol, cocaine and methamphetamine, ↑ rotarod performance ↓ depressive-like behaviour, ↓ D 1 agonist locomotor effect ↓ D 1 knockout low exploratory activity, loss of D 3 knockout phenotype 30% postnatal mortality rate, postural abnormalities, ↑ D2 knockout locomotor impairment Neonatal lethality due to respiration defect, craniofacial and cardiovascular defects Intestine distension, white spotted coat, premature death ↓ male fertility and testis size, ↓ sperm number and motility, ↓ testosterone levels, female sterility, ↓ ovary size, ↑ FSH levels Impaired circadian rhythm of locomotor activity, ↓ exploratory activity Hypertrophy of gastric mucosa, ↑ gastrin levels, ↑ parietal and enterochromaffin-like cells Impaired neutrophil and macrophage recruitment, ↓ inflammatory response, loss of platelet-activating factor anaphylaxis in females

[52]

129SvJxC57BL/6 Chemokine CCR7

Cmkbr7

129OlaxBALB/c

Chemokine CCR8

Cmkbr8

Chemokine CXCR2 Chemokine CXCR4

Cxcr2 Cxcr4

129SvxC57BL/6; 129Sv 129SvxC57BL/6 129SvJxC57BL/6

Chemokine CX 3 CR1

Cx3cr1

129SvxC57BL/6

Cholecystokinin CCK-A Cholecystokinin CCK-B/gastrin Dopamine D 1

Cckar Cckbr Drd1

129Sv 129SvxC57BL/6 129OlaxC57BL/6 129SvJaexC57BL/6

Dopamine D 2

Drd2

129SvxC57BL/6

129SvxBDF1

129SvxC57BL/6; N5 C57BL/6 129SvxC57BL/6

Dopamine D 2L

Drd2

129SvxC57BL/6

129SvxC57BL/6 N5 C57BL/6 129/SvJaexC57BL/6 129SvxC57BL/6

Dopamine D 3

Drd3

Dopamine D 4

Drd4

129SvxC57BL/6 129/OlaxC57BL/6

Dopamine D 5

Drd5

129SvJxC57BL/6

Dopamine D 1 /D 3 Dopamine D 2 /D 3 Endothelin ETA

Ednra

129SvEv

Endothelin ET B

Ednrb

129SvxC57BL/6

Follicle-stimulating hormone FSH-R

Fshr

129xC57BL/6

Histamine H1

Hrh1

129/OlaxC57BL/6

Histamine H2

Hrh2

129OlaxC57BL/6

Leukotriene B 4

Bltr

129SvJxC57BL/6

[329] [88] [44] [30] [188] [113] [156] [224] [339] [69] [7]

[346]

[140] [138]

[327]

[332] [1] [338] [138] [275] [119] [139] [138] [49] [122] [65]

[130] [153] [111]

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129

Table 1. Continued Receptor

Gene symbol

Genetic background

Phenotype

Reference

Lysophosphatidic acid LPA 1

lp A1 /vzg-1 /edg-2 Mc3r

129SvJxC57BL/6

↓ body weight, craniofacial deformity, 50% neonatal lethality due to suckling defect ↑ body fat, ↑ respiratory quotient on high fat diet, ↓ metabolism ↑ body fat, ↓ bone and body length, ↑ leptin and insulin levels, ↓ food intake in males Maturity onset obesity syndrome, ↑ food intake, ↑ insulin, glucose and leptin levels Body water repulsion and thermoregulation defects, ↓ sebaceous lipids, porphyrin deficiency ↓ central melatonin effects Loss of agonist-induced seizures, loss of agonist M-current K 1 channel regulation ↑ locomotor activity, ↑ rearing, ↑ striatal dopamine, ↑ amphetamine-induced locomotor activity ↓ body weight, ↑ locomotor activity, ↑ rearing ↓ agonist-induced tremor, salivation, hypothermia and analgesia ↓ female body weight, dilated pupils, ↓ agonistinduced salivation, distended urinary bladders, ↓ smooth muscle contractility ↓ body weight, ↓ body fat, ↓ food intake, ↓ insulin levels, ↓ leptin levels, ↓ propiomelanocortin and melanin-concentrating hormone expression ↑ locomotor activity, ↑ D 1 dopamine receptor locomotor responses ↑ deprivation-induced water consumption, ↓ stimulation-induced late phase dopamine release in nucleus accumbens ↓ agonist-induced striatal dopamine release, loss of acetylcholine-mediated cerebral vasodilation ↓ immune response, loss of agonist-induced neutrophil mobilization ↓ capsaicin inflammatory response, ↓ inflammatory response ↓ capsaicin inflammatory response, ↓ morphine and stress analgesia, ↓ aggressiveness ↓ anxiety, ↓ stress response, ↑ serotonergic transmission, ↓ serotonin autoreceptor function ↓ daily food intake, ↓ fast-induced refeeding, ↑ body fat, ↓ locomotor activity, ↑ insulin and leptin levels, ↓ metabolism ↑ body weight, ↑ insulin levels, ↓ metabolism, ↓ glucose-mediated insulin secretion Hyperalgesia, ↑ body weight, loss of NPY analgesic effect, loss of capsaicin inflammatory response ↑ body weight, ↑ body fat, ↑ food intake, ↓ leptin feeding inhibition Mild late-onset obesity, ↑ food intake, ↓ NPY-induced feeding No gross abnormalities Loss of supersensitivity to pentobarbital-induced sedation observed in Y2 2 / 2 mice Preservation of Y2 2 / 2 sedation phenotype ↑ anxiety, depressive-like behaviour, ↑ locomotor activity ↓ agonist spinal analgesia, loss of morphine analgesia tolerance ↓ agonist analgesia, loss of morphine analgesia and lethality ↑ proliferation of granulocyte-macrophage, erythroid and multipotential progenitor cells, ↓ locomotor activity, ↓ mating activity in males, ↓ sperm count and motility, ↓ litter size, loss of morphine response

[51]

Melanocortin MC3

129SvxC57BL/6 129SvJxC57BL/6

Melanocortin MC4

Mc4r

1293C57BL/6

Melanocortin MC5

Mc5r

Melatonin ML1A Muscarinic M1

Mtnr1a Chrm1

129SvEvTac; N7–N9 C57BL/6 129SvxC57BL/6 129SvJxC57BL/6 C57BL/6

Muscarinic M2

Chrm2

129SvEvxC57BL/6 129SvxCF-1

Muscarinic M3

Chrm3

129SvJxC57BL/6

129SvEvxC57BL/6; 129SvEv Muscarinic M4

Chrm4

129SvEvxCF-1

Muscarinic M5

Chrm5

129SvJxCD1 129SvEvxCF-1

N-formylpeptide FPR

Fpr1

129SvxC57BL/6

Neurokinin NK-1 (Substance P)

Tacr1

129SvxC57BL/6 129SvxC57/BL6 129/SvEv

Neuropeptide Y Y1

Npy1r

N5 C57BL/6 129OlaxC57BL/6 129SvxBalb/c

Neuropeptide Y Y2

Npy2r

129SvxBalb/c

Neuropeptide Y Y5

Npy5r

129SvxC57BL/6 129SvxBalb/c

Neuropeptide Y Y1/Y2 Neuropeptide Y Y2/Y5 Opioid d

Oprd1

129/SvxC57BL/6 129/SvEvxC57BL/6

Opioid m

Oprm1

129/OlaxC57BL/6 Swiss black

[29] [38] [126] [43] [183] [109] [98] [212] [102] [202]

[345]

[103] [349] [344] [93] [23] [63] [284] [251] [162] [230] [229] [198] [227] [227] [227] [85] [355] [185] [323]

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130 Table 1. Continued Receptor

Gene symbol

Genetic background

Phenotype

Reference

129SvEvxC57BL/6

Hyperalgesia in hot plate and tail flick tests, loss of morphine analgesia Loss of morphine analgesia, reward and withdrawal, ↓ locomotor activity Loss of morphine analgesia ↑ sensitivity to visceral pain, ↓ morphine withdrawal Loss of agonist binding sites Loss of nociceptin/orphanin FQ hyperalgesia and hypoactivity, hearing impairment ↑ lumphoid organs size, ↑ T and B lymphocytes, late onset auto-immune syndrome ↓ systemic anaphylactic response

[308]

129SvxC57BL/6

Opioid k Opioid m/d/k Orphanin FQ/Nociceptin

Oprk1

129SvEvxC57BL/6 129SvxC57BL/6

Ofqr

129SvxC57BL/6

Orphan G2A

G2a

N3–N6 Balb/c

Platelet-activating factor Prostacyclin

Ptafr

129OlaxC57BL/6

Ptgir

129OlaxC57BL/6

Prostanoid DP Prostanoid EP1 Prostanoid EP2

Ptgdr Ptger1 Ptger2

N5 C57BL/6 129OlaxC57BL/6 129SvEvxC57BL/6

Prostanoid EP3

Ptger3

129OlaxB6D2; 129Olax129SvEv 129OlaxC57BL/6

Prostanoid EP4 Prostanoid FP

Ptger4 Ptgfr

129OlaxC57BL/6 129OlaxC57BL/6

Purinoceptor P2Y1 Rhodopsin Serotonin 5-HT 1A

P2ry1 Rho Htr1a

129SvxC57BL/6 129SvxC57BL/6 129SvJxC57BL/6 129SvxSW 129Sv

Serotonin 5-HT 1B

Htr1b

129Sv-ter

Serotonin 5-HT 2B

Htr2b

129/PAS

Serotonin 5-HT 2C

Htr2c

129SvxC57BL/6

Serotonin 5-HT 5A Somatostatin sst 1

Htr5a sstr1

129Sv 129SvxC57BL/6

Somatostatin sst 2

sstr2

129Sv

Sphingosine-1-phosphate S1P1 Thrombin

edg-1 F2r/Par1

129SvxC57BL/6 129SvxC57BL/6

Thromboxane A 2

Tbxa2r

Vasopressin V2

Avpr2

129OlaxB6D2; 129Olax129SvEv 129SvJxC57BL/6

↑ thrombosis susceptibility, ↓ inflammatory and pain response Loss of ovalbumin asthmatic response No gross abnormalities ↓ litter size due to ovulation defect, ↑ systolic blood pressure, loss of agonist vasodilation Loss of urine osmolality increase in response to prostanoid production inhibition Lack of prostaglandin E 2 and interleukin-induced febrile response 95% neonatal death due to open ductus arteriosus Inability of fetus delivery at term, loss of oxytocininduced uterine contraction, loss of progesterone decline before parturition ↓ platelet aggregation, ↑ bleeding time, ↓ thrombosis Photoreceptor loss ↑ anxiety, ↓ depressive-like behaviour, loss of agonist hypothermia ↑ anxiety, ↓ depressive-like behaviour ↓ exploratory activity, ↑ anxiety, ↓ depressive-like behaviour ↑ aggressive behaviour, loss of 5-HT 1 agonist hyperlocomotor response Embryonic and neonatal lethality due to heart defects, severe ventricular hypoplasia ↑ body weight, ↑ body fat, loss of agonist food intake inhibition, epilepsy, premature death ↑ exploratory activity, ↓ LSD locomotor response Loss of agonist induced decrease in somatotroph growth hormone secretion, ↑ pituitary growth hormone levels Loss of growth hormone-induced inhibition of arcuate neurons Embryonic lethality due to hemorrhage 50% embryonic lethality, loss of thrombin response in fibroblasts ↑ bleeding time, ↓ platelet aggregation, loss of agonist Hemodynamic effect Loss of urine concentration ability, ↑ renal pelvic space, neonatal lethality due to hypernatremic dehydration

[205] [294] [301] [300] [237] [169] [131] [221] [203] [326] [142] [86] [326] [295] [313] [174] [125] [117] [249] [260] [286] [231] [319] [104] [158] [352] [184] [50] [321] [350]

The receptor names, gene symbols, genetic background of the mice used and phenotypes of the mutant mice reported in the original studies are shown. N3, N5 etc. correspond to the number of backcrosses into the host strain.

group has characterized the central effects of A 1 inactiva/2 tion and found that in hippocampal slices from A 2 mice, 1 the inhibitory effect of adenosine on glutamatergic transmission was absent and the attenuation in neuronal activity during, and functional recovery after hypoxia were reduced in the mutants, indicating that A 1 is involved in adenosine effects on excitatory neurotransmission in the hippocampus

and survival after hypoxia. The antinociceptive effect of an intrathecal adenosine analogue was absent, implicating the A 1 receptor in spinal analgesia, and anxiety-like behaviour in the light / dark box was increased in A 12 / 2 mice [134]. Two lines of mice lacking the A 2A receptor have been /2 generated [40,171]. A 2 mice exhibited a decrease in 2A exploratory behaviour in the open field test and increased

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131

Table 2 Mouse lines lacking the endogenous ligands for family 1 GPCRs Ligand Angiotensin I Angiotensinogen

Gene symbol

Genetic background

Phenotype

Reference

Agt

↓ systolic blood pressure

[318]

High neonatal lethality, kidney abnormalities ↓ blood pressure, kidney abnormalities ↑ pancreatic amylase levels, ↓ duodenal somatostatin levels, ↑ brain somatostatin levels

[144] [236] [164]

High embryonic lethality due to cardiovascular defects, motor impairments, neonatal lethality High embryonic lethality, bradycardia, neonatal lethality

[353]

Cholecystokinin

Cck

C57BL / 6xCBAx ICR 129OlaxC57BL / 6 129OlaxC57BL / 6 129SvJ

Dopamine Tyrosine hydroxylase

Th

129SvxC57BL / 6 129OlaxC57BL / 6

[152]

Dynorphins Prodynorphin

Pdyn

129SvEv-Tac 129xC57BL / 6

No gross abnormalities ↓ D9 -THC analgesia, loss of D9 -THC aversive effect

[297] [357]

b-endorphin Preopiomelanocortin Endothelin-1

Pomc Edn1 Edn-3

↑ body weight, loss of opioid stress-induced analgesia Neonatal lethality due to respiratory failure, craniofacial abnormalities White spotting of skin and coat, absence of melanin pigment, short life span

[274] [161]

Endothelin-3

129SvxC57BL / 6 129SvJxICR; 129SvJxC57BL / 6 129SvxC57BL / 6

Enkephalins Pre-proenkephalin

Penk2

129SvxCD1

[155]

Galanin

Gal

129 / OlaHsd

Follicle stimulating hormone

Fshb

129SvxC57BL / 6; 129SvEv

↑ anxiety, ↑ male aggressiveness, supraspinal hyperalgesia, ↓ locomotor activity ↓ pituitary prolactin levels, lactation failure, ↓ mammary gland development, ↓ estrogen lactotroph response ↓ testis size, ↓ sperm number and motility, female infertility, ↓ ovary and uterus size

Histamine Histidine decarboxylase Orexin Orphanin FQ / nociceptin

Hdc Hcrt Ofq

129SvxC57BL / 6 129SvEvxC57BL / 6 129OlaxC57BL / 6

Oxytocin Neurokinin Tachykinin 1

Oxt

129SvEvxC57BL / 6

Tac1

Neuropeptide Y

Npy

Noradrenaline and adrenaline Dopamine b-hydroxylase

Dbh

[10]

[335] [159]

↓ number of mast cells, altered mast cell morphology Narcolepsy during dark cycle, ↑ REM sleep ↑ anxiety levels, hypoalgesia, ↑ stress sensitivity, ↑ plasma corticosterone levels Nursing failure in females leading to offspring lethality

[244] [37] [157]

129xCD-1 129xC57BL / 6 129SvxC57BL / 6

Hypoalgesia, ↓ capsaicin inflammatory response Hypoalgesia in hot plate and formalin pain tests ↑ susceptibility to GABA antagonist seizures, ↑ leptin feeding suppression

[32] [358] [83]

High embryonic lethality, ↓ body weight, ptosis

[322]

Pomc

129SvxC57BL / 6; 129SvCPJ 129Sv

↑ body weight, ↑ leptin levels, impaired adrenal development, altered pigmentation

[348]

Ptgds

129 / OlaxC57BL / 6

[75]

Prostaglandin synthase 1 (cyclooxygenase 1)

Ptgs1

129OlaxC57BL / 6

Prostaglandin synthase 2 (cyclooxygenase 2) Somatostatin

Ptgs2

129OlaxC57BL / 6

Smst

N5 C57BL / 6

Loss of prostaglandin E2 and ↓ GABAA antagonist allodynia ↓ prostaglandin PGE 2 levels, ↓ platelet aggregation, ↓ arachidonic acid inflammatory response, low mutant survival rate Nephropathy leading to ↑ lethality, ↑ susceptibility to peritonitis Changes in somatostatin receptor SSTR1, SSTR2 and SSTR5 levels, ↓ pituitary growth hormone levels, male hepatic feminization

Thrombin Prothrombin

F2

129 / OlaxBlack Swiss

Partial embryonic lethality, hemorrhage, neonatal lethality

[315]

Preopiomelanocortin-derived peptides Prostaglandin Prostaglandin D2 synthase

[238]

[167]

[219] [186]

Genes encoding the ligands, the enzymes involved in the ligand synthesis or the ligand precursors have been inactivated. Gene symbols of the inactivated protein, the genetic background and the phenotypes of the mutant mice as described in the original reports are shown.

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levels of anxiety as measured using the plus maze and /2 light / dark box tests. In addition, A 2 mice showed 2A hypoalgesia and male mutants displayed higher levels of aggressiveness towards intruders [171]. Studies by another group using separately generated A 2A mutants have found that inactivation of the A 2A receptor resulted in protection against brain damage induced by transient focal ischemia suggesting an important role of A 2A receptor in neuro/2 protection [40]. A 2 mice also exhibited reduced toxicity 2A in the MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxin model of Parkinson’s disease [42]. The locomotor stimulant effect of caffeine was absent in /2 A2 mice indicating that blockade of the A 2A receptor is 2A responsible for the effects of caffeine at low doses [42,76,171]. A 2A mutants were less susceptible to ethanol withdrawal-induced seizures [79] and they demonstrated reduced depressive-like behaviour in the tail suspension /2 and forced swim tests [77]. A 2 mice exhibited a 2A decrease in basal locomotor activity as well as a decrease in psychostimulant-induced locomotor response despite normal expression of dopamine receptors and unaltered dopaminergic innervation [39]. However, another group 2/2 reported that A 2A mice demonstrated a striatal hypodopaminergic phenotype with reduced striatal extracellular dopamine levels and higher dopamine D 1 and D 2 receptor mRNA levels [62]. The same study reported that A 2A mutants exhibited higher striatal extracellular glutamate levels, reduced substance P and enkephalin mRNA levels and increased mRNA expression of a glutamic acid decarboxylase isoform (GAD 67) as well as lower striatal, cortical and hippocampal expression of immediate early genes zif268 and arc mRNAs, indicating that A 2A is involved in many aspects of neuronal activity. The effects of caffeine on the expression of immediate early genes, enkephalin and substance P were also altered in some brain /2 areas of A 2 mice. Instead of a biphasic effect observed 2A in wild-type mice with a decrease and increase in expression following low and high caffeine doses, respectively, A 2A mutants exhibited a monophasic effect leading to an increase in expression [61]. Other neurochemical changes /2 found in some brain areas of A 2 mice included slightly 2A reduced adenosine transporter density, a small increase in A 1 receptor density [304] and increased AMPA receptor binding sites [305], indicating changes in adenosine and glutamatergic systems. Adenosine A 2A receptors co-localize postsynaptically with dopamine D 2 receptors and antagonistic interactions between these two receptors have been reported [264]. Evidence for such interactions has also been demonstrated in studies using both A 2A and D 2 as well as A 2A / D 2 receptor double mutant mice. At the cellular level, concurrent A 2A / D 2 receptor inactivation partially reversed the increase in enkephalin mRNA expression in striatopallidal neurons that was observed in mice lacking only the D 2 receptor [41]. In addition, catalepsy induced by halo2/2 peridol, a D 2 antagonist, was attenuated in A 2A mice

[41], a finding that was also reported by another group studying an independently engineered strain of A 2A mutant mice [78]. The same group also demonstrated that catalepsy induced by either a dopamine D 1 receptor antagonist or a muscarinic receptor agonist was also /2 reduced in A 2 mice. 2A

2.2. Adrenergic receptors The catecholamines norepinephrine and epinephrine are widely distributed throughout the periphery and the CNS and are involved in many physiological functions. Three classes of adrenergic receptors have been identified, a 1 (a 1A , a 1B , and a 1D ), a 2 (a 2A , a 2B and a 2C ) and b (b 1 , b 2 and b 3 ). Brain areas expressing specific adrenergic receptors include the cerebral cortex, cerebellum, striatum, thalamus, hippocampus and olfactory tubercle [235]. In addition to their important role in peripheral function, the adrenergic receptors are involved in behavioural effects including locomotor activity, learning and memory. Inactivation of the a 1B gene caused 42% and 32% decrease in total a 1 binding sites in the cerebral cortex and cerebellum, respectively [35]. Mice lacking the a 1B receptor exhibited reduced exploratory activity in an open field test and impaired passive avoidance learning [149]. 2/2 However, studies by another group have shown that a 1B mice displayed an increase in exploratory activity in response to a novel environment assessed in the emergence, open field and novel object tests as well as an impairment in spatial learning demonstrated in the water maze task [309]. Mice deficient in the a 2A receptor exhibited increased immobility time in the forced swim test, indicating enhanced depressive-like behaviour [293]. The same study reported that the effects of a tricyclic antidepressant acting /2 on the norepinephrine transporter were absent in a 2 2A 2/2 mice. In addition, a 2A mice displayed reduced rearing behaviour in an open field and increased time spent in the dark compartment of the light / dark box after injection stress, indicating higher anxiety levels. Mice lacking the a 2C receptor demonstrated reduced hypothermia induced by the a 2 agonist dexmedetomidine [282]. The effects of the same agonist on spatial memory /2 improvement were also reduced in a 2 mice [317]. 2C Increased aggressiveness as well as changes in sensorimotor gating exhibited by enhanced startle response and reduced prepulse inhibition were observed in a 2C mutants [280]. Depressive-like behaviour in the forced swim test was attenuated and stress-induced corticosterone 2/2 levels were lower in a 2C mice [279]. At the cellular 2/2 level, a 2C mice exhibited higher cortical and hippocampal immediate early gene c-fos and junB levels [279]. /2 Most of the changes found in a 2 mice were opposite to 2C those found in mice overexpressing a 2C receptors [279– 282], indicating specific involvement of the a 2C receptor in

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these processes. Dopamine metabolite levels were reduced [282], amphetamine-induced locomotor stimulant response was enhanced [281] and a dopamine re-uptake blocker caused an increase in the number of total responses for /2 food reward in an operant test in a 2 mice [129], 2C indicating some changes in dopaminergic function in a 2C mutants. Mice deficient in both a 2A and a 2C receptors have been generated by interbreeding of mice lacking each receptor alone [115]. The a 2 receptor agonist-mediated inhibition of serotonin release was reduced in hippocampal slices from /2 /2 both a 2 mice and a 2 mice and was completely 2A 2C 2/2 2/2 abolished in slices from a 2A a 2C mice, suggesting the involvement of presynaptic a 2A and a 2C , but not a 2B receptors, in a 2 receptor-mediated serotonin inhibition [289].

2.3. Bombesin-like peptide receptors Bombesin-like peptides are widely distributed in the periphery and the CNS and are thought to be involved in exocrine and endocrine functions, smooth muscle contraction, feeding and behaviour [208,240]. The receptors for bombesin-like peptides include the gastrin-releasing peptide receptor (GRP-R), neuromedin B receptor (NMB-R) and bombesin receptor subtype-3 (BRS-3). These receptors are expressed in the periphery and the CNS including the olfactory, thalamic and hypothalamic regions [9,242]. Two independent groups have reported the generation of GRP-R deficient mice [110,330]. GRP-R2 / 2 mice exhibited increased locomotor activity and non-aggressive social responses [330]. The same group later showed that the higher social responsiveness was observed in both male [343] and female [342] GRP-R mutants. Another group reported that the satiety response induced by bombesin and measured by decreased glucose intake was absent in GRPR2 / 2 mice, indicating that GRP-R is involved in the control of food intake [110]. Mice deficient in the NMB-R exhibited a decrease in neuromedin B-mediated hypothermia, indicating that the receptor is involved in thermoregulation [241]. Mice lacking BRS-3 exhibited hyperphagia, mild obesity [243], increased preference for sweet solution and aversion for bitter solution [341] suggesting a role for BRS-3 in obesity and taste preference. Further studies indicated that BRS-3 2 / 2 mice exhibited altered responses to social isolation [340]. Under isolation housing conditions, BRS-3 mutants exhibited higher food intake and body weight, and a decrease in non-aggressive response in a social interaction test. Isolation-induced locomotor activity stimulation was absent in BRS-3 2 / 2 mice.

2.4. Cannabinoid receptors Cannabinoid receptors CB 1 and CB 2 are the site of

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action of D9 -tetrahydrocannabinol (D9 -THC), the active ingredient in marijuana, as well as the endogenous ligand anandamide. The CB 1 receptor is distributed in the CNS in areas including the cerebellum, hippocampus and basal ganglia, and is thought to be involved in movement control and memory processes, and the CB 2 receptor is expressed in the periphery [84]. Two lines of mice lacking the CB 1 receptor have been /2 generated [170,359]. CB 2 mice exhibited an increase in 1 exploratory activity in an open field and normal nociceptive thresholds in thermal, chemical and mechanical pain /2 tests [170,328]. However, studies using another CB 2 1 mouse model reported a decrease in open field activity, increased immobility in the ring catalepsy test and higher nociceptive thresholds in the hot plate and formalin tests [310,359]. The analgesic, hypothermic and locomotor depressant effects of D9 -THC were absent in both strains /2 of CB 2 [170,359]. The cannabinoid agonist WIN55,2121 2 was not self-administered by CB 1 mutants indicating that the reinforcing properties of cannabinoids were also absent [170]. Memory in an object recognition task [262] and long-term potentiation in hippocampal slices [15] were /2 enhanced in CB 2 mice. Neurochemical analysis of 1 neurons in the striatum, where the CB 1 receptor is expressed at high levels, showed that dynorphin, substance P, enkephalin and the glutamic acid decarboxylase GAD /2 67 mRNA levels were elevated in CB 2 mice [310]. 1 Endogenous cannabinoid [334] and cannabinoid agonistinduced [107] decrease in inhibitory GABAergic synaptic transmission was absent in hippocampal slices from /2 CB 2 mice indicating that presynaptic CB 1 receptor is 1 involved in the regulation of GABA release. CB 1 receptordeficient mice have been used to study cannabinoid / opioid interactions. The rewarding and withdrawal properties of the opioid agonist morphine were reduced [53,170,178] and morphine-mediated dopamine release [201] as well as opioid k receptor-induced dysphoric effects [170] were /2 absent in CB 2 mice. Opioid receptor agonist-mediated 1 antinociceptive responses in thermal pain tests were normal but opioid-dependent, stress-induced analgesia was attenuated in CB 1 mutants [328]. Further studies have shown that in addition to the absence of morphine reward, chronic morphine-induced locomotor sensitization was abolished but cocaine-induced locomotor sensitization and /2 reward were intact in CB 2 mice [199]. 1

2.5. Dopamine receptors Dopamine, one of the major neurotransmitters in the CNS, mediates its effects through activation of five dopamine receptors (D 1 –D 5 ). These receptors are abundant throughout the CNS and the periphery. In addition to their multiple peripheral functions, dopamine receptors are important in the regulation of motor behaviour, learning and memory, motivation and reward [211]. As with other receptor systems, the lack of highly selective ligands has

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hindered the elucidation of the contribution of each dopamine receptor subtype in specific behaviours. Hence, mice deficient in each of the dopamine receptors have been studied extensively [101,331]. Two independently generated lines of D 1 receptor-deficient mice have been reported [69,339]. The expression of basal striatal dynorphin and substance P, which are co-localized in D 1 containing neurons, was reduced in D 12 / 2 mice implicating the D 1 receptor in the regulation of expression of these neuropeptides [69,70,339]. D 12 / 2 mice demonstrated a loss of dopamine as well as D 1 and D 2 agonist-mediated inhibition of glutamate-induced firing of nucleus accumbens neurons [337], higher striatal dopamine levels [81,246], lower dopamine metabolite DOPAC (3,4dihydroxyphenylacetic acid) levels and reduced number of dopaminergic neurons in substantia nigra pars compacta [246] implicating the D 1 receptor in regulation of neuronal function and dopamine levels. Conflicting findings were /2 reported with respect to the locomotor phenotype of D 2 1 mice. They were found to exhibit either no changes [80,139] or an increase in spontaneous and novelty-induced locomotor activity [47,337,339]. However, several reports including findings from our laboratory indicated that D 1 receptor mutant mice displayed reduced exploratory activity in an open field when measured as both horizontal activity and rearing behaviour [69,139,303]. D1 2 / 2 mice displayed a decrease in both grooming time and completion of the grooming syntax [59,68,337] in addition to a reduction of novelty-induced grooming following the administration of several neuropeptides [68]. However, an increase in grooming behaviour has also been /2 reported [47]. D 2 mice exhibited a lack of response to 1 both the locomotor-stimulant effects of a D 1 agonist and the motor-depressant effects of a D 1 antagonist [339]. Dopamine receptors are involved in mediating the locomotor and rewarding effects of psychostimulants and some effects induced by either cocaine or amphetamine were reduced or abolished in D 1 mutants. Acute and chronic cocaine administration failed to produce an in/2 crease in locomotor and stereotyped activity in D 2 mice 1 over a wide range of doses, and suppressed activity at higher doses [70,336,337]. The amphetamine locomotorstimulant effect was also attenuated in D 12 / 2 mice /2 [56,336]. D 2 mice exhibited reduced cocaine-mediated 1 inhibition of firing of nucleus accumbens neurons [337] and an absence of psychostimulant-induced expression of dynorphin and immediate early genes c-fos, zif268 and /2 junB [70,218]. Although D 2 mice displayed retained 1 cocaine reward in the conditioned place preference (CPP) paradigm [210], an attenuation in alcohol-seeking behaviour was observed [81]. Morphine-induced locomotor sensitization was absent, low morphine dose-induced analgesia was potentiated and striatal m opioid receptor immunoreactivity was reduced in D 1 mutants [11] indicating changes in opioid function in response to D 1 inactivation. /2 D2 mice showed impairments in locating the escape 1

platform in the water maze, a test for spatial learning [80,139,303], but they exhibited prolonged retention and delayed extinction of conditioned fear responses in two separate tasks [82]. D 1 mutants demonstrated impairments in response initiation to various stimuli, including a visual stimulus [303], a novel open field and the rotarod [139]. The behavioural effects of the NMDA receptor antagonist ketamine were reduced [213] and the number of NMDA 2/2 receptors was decreased in D 1 mice [4] suggesting a role for D 1 in interactions of dopaminergic and glutamatergic neurotransmission. Mice lacking the D 2 receptor were generated in four independent laboratories [7,138,140,346]. D 22 / 2 mice exhibited various neurochemical changes including an increase in striatal enkephalin mRNA [7,138,222,346], a decrease in striatal substance P expression [7,222], loss of D 2 autoreceptor function [163,209,346], increases in dopamine metabolites DOPAC and HVA (homovanillic acid) levels [138,246], an increase or decrease in glutamic acid decarboxylase expression depending on brain region [7,222], a decrease in glial cell line-derived neurotrophic factor (GDNF) and neurotrophin-4 expression [24], a decrease in dopamine transporter function [64] and an increase in spontaneous GABA release from striatopallidal neurons [351]. The number of dopaminergic neurons in substantia nigra pars compacta was lower but the density of dopaminergic terminals in the striatum was higher in /2 D2 mice, suggesting a role for D 2 in regulation of 2 terminal density [246]. One group reported that the striatal levels of D 3 receptor protein were higher [138] and the striatal cellular distribution pattern of the neurochemical differentiation marker calbindin was altered in D 2 mutants [136]. The above findings underline the importance of the D 2 receptor in the regulation of normal neuronal activity and expression of neuropeptides and proteins in the CNS. Stimulation of corticostriatal fibers induced an NMDA/2 dependent long-term potentiation in D 2 mice as opposed 2 to a long-term depression observed in wild-type mice, indicating abnormalities in synaptic plasticity caused by D 2 inactivation [31]. D 1 agonist-induced c-fos expression was attenuated in D 22 / 2 mice, suggesting that D 2 is required for maximum D 1 -mediated c-fos induction [137]. However, the decreased c-fos response was reversed by pretreatment with either methamphetamine or a full D 1 agonist [291]. D 2 mutant mice exhibited an increase in corticostriatal glutamate transmission [36] and they were found to develop glutamate-induced seizures that led to hippocampal cell death at kainic acid doses that were not epileptogenic for wild-type mice [25], implicating the D 2 receptor in inhibition of glutamatergic neurotransmission. Amphetamine-induced decrease of stimulation-dependent release of vesicular dopamine was reduced in striatal slices /2 from D 2 mice emphasizing the role of D 2 as an 2 autoreceptor [292]. /2 Behavioural studies reported that D 2 mice exhibited 2 reduced locomotor activity and rearing [7,46,48,138,346],

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postural abnormalities [7,138], an impairment in rotarod performance and cataleptic-like behaviour [7]. However, the performance in the locomotor and rotarod tests was affected in part by the genetic background [141]. Studies of D 2 /A 2A receptor interactions found that the locomotor impairment and changes in enkephalin and substance P /2 expression in D 2 mice were reversed with an adenosine 2 A 2A receptor antagonist administration [3]. Normal A 2A receptor signaling via the cAMP pathway was found to be disrupted, A 2A -mediated enhancement of GABA release was eliminated and the caffeine-induced stimulation of /2 locomotor activity was reduced in D 2 mutants [351]. D 2 2 mice were insensitive to the locomotor and hypothermic effects of some putative dopamine D 2 -like receptor agonists [19,46,48] demonstrating the selectivity of these ligands for the D 2 receptor. D-Amphetamine, an indirect dopaminergic agonist, failed to disrupt the prepulse inhibition in D 2 receptor mutant mice suggesting that D 2 is involved in the amphetamine-mediated effect on sensorimotor gating [259]. Morphine reward in the CPP test /2 was absent in D 2 mice although opioid locomotor2 stimulant effect, morphine-induced physical dependence and withdrawal as well as food reward were still present [191]. Another report suggested that the absence of morphine reward was found only in opiate-dependent and withdrawn D 2 mutants [67]. D 22 / 2 mice demonstrated enhanced supraspinal m and k opioid receptor-mediated analgesia and increased spinal orphanin FQ / nociceptin (OFQ / N) receptor-induced analgesia [145], suggesting a role for the D 2 receptor in modulation of opioid and /2 OFQ / N nociception. D 2 mice exhibited attenuated 2 ethanol-induced locomotor impairment and decreased ethanol reward in free choice [253], self-administration [266] and CPP paradigms [60]. Recently, the generation of mice lacking only the long form of the D 2 receptor (D 2L ) but expressing the short form D 2S has been reported by two groups [327,332]. D 2S 2/2 receptor mRNA was found to be upregulated in D 2L mice [327,332]. One group reported no changes in either spontaneous or novelty-induced locomotor activity [327], however the second group found a reduction in locomotor /2 activity and rearing in a novel environment in D 2 mice 2L [332]. Presynaptic D 2 receptor-induced decrease in locomotor activity was preserved [327] but haloperidolinduced catalepsy, thought to be mediated by postsynaptic D 2 receptors, was absent [327,332] and haloperidol-induced decrease in locomotion was reduced [332] in D 2L mutants. The locomotor stimulating effects of D 1 agonists /2 were decreased in D 2 mice suggesting some impair2L ments in D 1 receptor signalling [327]. Three lines of D 3 receptor-deficient mice were generated /2 by independent laboratories [1,138,338]. D 2 mice ex3 hibited increased exploratory activity in a novel environment as measured by horizontal activity and rearing behaviour [1,338], although basal locomotor activity was normal [138,139]. D 3 mutant mice displayed enhanced

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sensitivity to locomotor stimulation induced by concurrent D 1 / D 2 receptor agonist administration and low doses of cocaine, as well as increased sensitivity to the rewarding properties of amphetamine in the CPP paradigm [338]. The expression of c-fos and dynorphin in response to acute but not chronic cocaine administration were increased in the /2 striatum of D 3 mutants [34]. D 2 mice were found to 3 have reduced anxiety levels in the open field and elevated plus maze tests [139,311] although another group reported no changes in the plus maze during a shorter test session [338]. The basal extracellular levels of dopamine were higher in D 3 mutants, suggesting the involvement of D 3 receptor in dopamine release [154]. D 1 -induced c-fos expression was attenuated in D 3 mutants and was further reduced in response to a D 2 antagonist suggesting that both D 2 and D 3 are required for maximum D 1 -mediated c-fos effect [137]. As with the D 2 receptor mutants, the decreased c-fos response was reversed by pretreatment with /2 methamphetamine or a full D 1 agonist [291]. D 2 mice 3 were found to express lower calbindin immunoreactivity in nucleus accumbens, a brain region expressing high levels of D 3 receptor, indicating that D 3 may regulate calbindin expression [136]. Mice lacking the D 4 receptor exhibited decreased spontaneous locomotor activity, exploratory behaviour and movement initiation and improved performance on the rotarod [275]. The same study reported that the locomotorstimulant effects of ethanol, cocaine and methamphetamine were increased in D 4 mutants demonstrating the involvement of D 4 in drug-induced locomotion. D 42 / 2 mice displayed attenuated exploratory activity as measured in the open field, emergence and novel object tests, suggesting a role for the D 4 receptor in novelty-seeking behaviour [71]. D4 2 / 2 mice showed increased dopamine synthesis and turnover in the striatum [275], lower glutamate immunoreactivity in frontal cortex and increased cortical excitability indicating that D 4 may modulate neuronal activity [273]. In addition, D 4 mutants were more sensitive to the convulsant effects of the GABAA receptor antagonist bicuculline suggesting an inhibitory role for the D 4 receptor in GABAergic activity [273]. Recently, mice lacking the D 5 receptor were reported to exhibit normal locomotor activity, rotarod performance, anxiety, fear conditioning, sensorimotor gating and spatial learning in the water maze [119]. The same study reported /2 that in the forced swim test, male D 2 mice demonstrated 5 lower levels of immobility indicating reduced depressivelike behaviour, although no changes were observed in female mutants. The locomotor-stimulant effects of the D 1 / D 5 agonist SKF 81297 were decreased but the locomotor-depressant effect of the D 1 / D 5 antagonist SCH 23390 was normal in D 5 mutants, suggesting some changes in D 1 receptor signaling. Finally, mice lacking multiple dopamine receptors have been produced. Mice deficient in both the D 2 and D 3 receptors exhibited a phenotype similar to that of mice

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lacking D 2 receptor or a combination of D 2 and D 3 mutant phenotypes [136–138]. D 22 / 2 D 32 / 2 mice exhibited postural abnormalities and an impairment in locomotor activity that was greater than that observed in D 2 single mutants. Similarly, D 22 / 2 D 32 / 2 mice displayed an increase in dopamine metabolite levels that was even higher than that of /2 D2 mice [138]. These findings suggest an additive effect 2 of concurrent D 2 and D 3 receptor inactivation on the locomotor and dopaminergic activity phenotype of D 2 single mutants. Mice deficient in both D 1 and D 3 receptors exhibited an attenuation of exploratory activity in an open field that was even lower than that observed in D 1 mutants [139]. In addition, the exploratory hyperactivity and anxiolytic-like /2 behaviour observed in D 2 mice were abolished in 3 2/2 2/2 D1 D3 mice, indicating that the presence of the D 1 receptor was necessary for the expression of some aspects of the D 3 mutant phenotype.

2.6. Histamine receptors In addition to its significant role in the periphery, histamine acts as a neurotransmitter and is involved in the regulation of hormonal function, circadian rhythm, food intake, body temperature control and locomotor activity. Four histamine receptors have been identified (H 1 –H 4 ). In addition to peripheral expression, H 1 , H 2 and H 3 receptors are distributed in brain areas such as cortex, hypothalamus, hippocampus, amygdala and basal ganglia [26]. The recently discovered H 4 receptor has been reported to be distributed in the periphery with low expression in the CNS [182,220,226,234,239,356]. H 1 receptor-deficient mice displayed abnormal circadian rhythm of locomotor activity with increased activity during the light cycle and lower activity during the dark cycle as well as decreased exploratory activity in a novel environment [130]. Further reports indicated that H 12 / 2 mice demonstrated lower levels of anxiety and aggressiveness [347] and they were found to be less sensitive to pain as measured by a variety of thermal, mechanical and chemical nociceptive tests [215,347]. Neurochemical analysis showed that cortical levels of dopamine and its metabolites were higher, and the turnover rates of dopamine and /2 serotonin were increased in H 2 mice indicating changes 1 in monamine activity [215,347]. Fat deposition in response to a high fat diet was more rapid and the suppression of feeding behaviour induced by leptin was attenuated in H 1 mutants demonstrating the involvement of H 1 in regulation of feeding behaviour [200]. A sleep–wake study found that the orexin A-mediated increase in wakefulness was /2 abolished in H 2 mice implying a role for the histaminer1 gic system and the H 1 receptor in the arousal effect of orexin A [124].

2.7. Muscarinic receptors Five muscarinic receptors M 1 –M 5 have been identified

and they display widespread expression throughout the CNS and the periphery [74,177]. Central muscarinic acetylcholine receptors are important in the regulation of movement control, cognitive function, nociception and body temperature. The study of the roles of individual muscarinic receptors in behaviour has been hindered by the lack of specific pharmacological agents and mice lacking each of the muscarinic receptors have been generated. Three independent groups have reported the generation /2 of mice deficient in the M 1 receptor [98,109,212]. M 2 1 mice were found to be resistant to the epileptic seizures induced by the muscarinic agonist pilocarpine [109]. Electrophysiological studies indicated that the slow voltage-independent inhibition of Ca 21 channels induced by a /2 muscarinic agonist was absent in neurons from M 2 1 mice, demonstrating the involvement of the M 1 receptor in this effect [296]. M 1 mutants exhibited an increase in horizontal locomotor activity and rearing in several tests [98,212], which could be a result of increased basal striatal /2 dopamine levels in M 2 mice [98]. In addition, amphet1 amine-induced locomotor activity was higher in M 1 mutants [98]. M 12 / 2 mice also displayed decreased anxiety, an increase in social interaction, reduced depressive-like behaviour in the forced swim test and impairments in fear conditioning and eight-arm radial maze, although these changes were caused most likely by the hyperactivity phenotype of the mutants [212]. Mice lacking the M 2 receptor showed an absence of tremor and akinesia induced by the nonselective muscarinic agonist oxotremorine [102]. The same study also reported that M 22 / 2 mice exhibited an attenuation in the agonist-induced salivary secretion, hypothermia as well as antinociceptive effects measured by the tail flick and hot plate tests. The muscarinic receptor-mediated fast voltagedependent regulation of Ca 21 channels was absent in /2 M2 mice, implicating the M 2 receptor in this effect 2 [296]. Two groups have reported the generation of mice lacking the M 3 receptor [202,345]. M 32 / 2 mice exhibited lower body weight [202,345] in addition to reduced body fat and leptin levels as well as lower food intake [345], indicating that M 3 is involved in regulation of feeding behaviour. M 4 receptor-deficient mice demonstrated an increase in spontaneous locomotor activity [103]. The same study found that the locomotor stimulatory effects of the nonselective dopaminergic agonist apomorphine and the dopamine D 1 receptor selective agonist SKF38393 were enhanced in M 42 / 2 mice suggesting that D 1 -mediated locomotor effects are potentiated in these mutants. Two groups have recently reported the generation of mice with inactivated M 5 receptors [344,349]. M 52 / 2 mice exhibited an increase in water consumption following water deprivation [349]. The late phase of dopamine release in the nucleus accumbens induced by electrical stimulation was absent in M 5 mutants [349], and muscarinic agonist-induced dopamine release was decreased in

J.M. Karasinska et al. / Brain Research Reviews 41 (2003) 125–152 /2 striatal slices from M 2 mice [344] suggesting a role for 5 the M 5 receptor in mediating dopamine release.

2.8. Neurokinin receptors The neurokinins substance P, neurokinin A (substance K) and neurokinin B (neuromedin K) are involved in nociception, stress response, mood and anxiety. The neurokinin receptors (also called tachykinin receptors) NK 1 , NK 2 and NK 3 mediate the actions of neurokinins and are distributed throughout the brain and spinal cord [112,312]. Mice lacking the substance P receptor NK 1 were developed in three independent laboratories [23,63,284]. /2 An electrophysiological study found that NK 2 mice 1 exhibited a lack of response amplification to an increasingly noxious mechanical stimulus measured by electromyog/2 raphic activity [63]. NK 2 mice also demonstrated 1 hypoalgesia in the formalin [63,146] as well as other chemical, thermal and mechanical pain tests [146,165,196], reduced morphine and stress-induced analgesia [63] and a decrease in capsaicin and nerve injury-induced hyperalgesia [166,195,196]. Noxious stimulus-induced Fos expression in raphe nuclei was attenuated in NK 1 mutants, suggesting that the descending inhibitory control of noxiously evoked response was reduced [13]. The findings of the above studies have emphasized the role of substance P and NK 1 receptor in pain response. Morphine-induced /2 locomotion, reward and withdrawal were absent in NK 2 1 mice although cocaine reward in the CPP was normal, indicating that the NK 1 receptor plays a role in opiate reward [223]. NK 1 mutants displayed an increase in the firing rate of dorsal raphe nucleus, reduced levels of serotonin 5-HT 1A receptor mRNA and binding sites in the same brain region and downregulation of presynaptic 5HT 1A receptor function, suggesting an interaction between NK 1 and serotonergic neurotransmission [90,284]. Selective serotonin reuptake inhibitor-mediated increase in /2 extracellular cortical serotonin levels was higher in NK 2 1 mice [90]. NK 1 mutants were reported to exhibit reduced aggressiveness and either no changes [63] or a decrease in anxiety levels in the elevated plus maze and noveltysuppressed feeding test [284]. Reduced anxiety was also observed in NK 1 mutant pups and was exhibited by a decrease in ultrasonic vocalization following maternal separation [276,284].

2.9. Neuropeptide Y receptors The neurotransmitter neuropeptide Y (NPY) is involved in the regulation of peripheral and central function including antinociception, food intake and circadian rhythm. Five neuropeptide Y receptors have been identified, Y 1 , Y 2 , Y 4 , Y 5 and Y 6 , and they are expressed in brain areas including the cerebral cortex, islands of Calleja, hippocampus, hypothalamus, substantia nigra and the brain stem [92,168]. Three lines of mice deficient in Y 1 receptor have been

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generated [162,230,251]. Y 1 mutants exhibited lower activity levels during both the light and dark cycles [251] and an increase in body weight that was more pronounced in female mutants, accompanied by a reduced metabolic rate and higher insulin, free fatty acid and leptin levels [162,230,251]. Food intake was found to be either normal when measured on a weekly basis [162] or attenuated when measured daily [251] and the refeeding response was /2 decreased in Y 12 / 2 mice [251]. Y 2 mice demonstrated 1 hyperalgesia in the hot plate, tail flick, formalin and mechanical pain tests and the analgesic effect of NPY was absent in Y 1 mutants [230]. Additional studies reported /2 that Y 2 mice exhibited reduced duration of sedation 1 induced by the GABAergic agonist pentobarbital and absence of NPY-mediated potentiation of sedation induced by several anaesthetics, implicating the Y 1 receptor in regulation of sedation [228]. Mice lacking the Y 2 receptor exhibited increased body weight, body fat, higher food consumption and lower energy expenditure [229]. The same study reported that NPY-induced feeding was normal but leptin-induced re/2 duction in feeding was attenuated in Y 2 mice, indicating 2 that Y 2 is involved in the regulation of body weight and /2 food intake. In contrast to Y 2 mice, pentobarbital-in1 duced sedation was prolonged and the NPY-mediated /2 potentiation of this effect was increased in Y 2 mice 2 [227] suggesting that NPY modulates GABAergic-induced sedation in opposing fashion depending on the receptor. /2 However, Y 2 mice demonstrated a decrease in NPY2 mediated potentiation of sedation induced by the NMDA antagonist ketamine [227]. Two lines of mice lacking the Y 5 receptor have been generated [198,227]. One group reported increased body weight and body fat, higher food intake and attenuation of the feeding response induced by NPY and related endogen2/2 ous peptides in Y 5 mice [198]. Further studies found 2/2 that Y 5 mice exhibited higher sensitivity to kainic acidinduced seizures, an effect that was influenced by the genetic background [197]. The same study found that NPY-induced anticonvulsant actions were absent in the /2 Y2 brain hippocampal slices, implicating the Y 5 re5 ceptor in modulation of NPY-mediated antiepileptic actions. Y 5 mutants were more sensitive to the sedative effects of ethanol, possibly due to higher plasma ethanol levels following ethanol administration [320]. /2 2/2 /2 2/2 Recently, the generation of Y 2 Y2 and Y 2 Y5 1 2 double mutants has been reported [227]. The increase in /2 pentobarbital-induced sedation observed in Y 2 mice was 2 2/2 2/2 completely abolished in Y 1 Y 2 double mutants but still present in Y 22 / 2 Y 52 / 2 mice indicating that the presence of Y 1 , but not Y 5 , is required for this effect. In /2 2/2 addition, Y 2 Y2 mice displayed a decrease in 1 ketamine-induced sedation although this response was not /2 observed in either Y 2 or Y 22 / 2 single mutants, sug1 gesting that the presence of at least one of the receptors is required for the full response to ketamine.

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2.10. Opioid receptors The three receptors for endogenous opioids: m, d and k are widely distributed throughout the brain. These receptors mediate the effects of opioids on learning and memory, feeding behaviour, thermoregulation and the regulation of pain perception including the mediation of the analgesic effects of morphine [135,175]. To date, several lines of mice lacking each of the opioid receptors have been produced [143]. Five independent laboratories have reported the generation of m receptor-deficient mice [185,205,294,308,323]. Although nociceptive thresholds in the tail-flick and hot plate tests were found to be either unchanged [205] or slightly decreased [308] in m2 / 2 mice, morphine-induced analgesia, reward and physical dependence were completely abolished [91,185,205,294,306,308,323], implicating the m receptor in the analgesic, reinforcing and adverse effects of morphine. Moreover, morphine-induced locomotor activity [306,323], respiratory depression [206], immunosuppression [96] and high dose-induced lethality [185] were absent in m2 / 2 mice. Morphine-induced potentiation of pentobarbital-mediated responses including the loss of righting reflex and hypothermia [248] and apomorphinemediated climbing behaviour [133] were also absent in m2 / 2 mice, implicating the m receptor in the synergistic effects of morphine and the GABAergic and dopaminergic agonists. The analgesic effects of the m receptor endogenous ligands endomorphin-1 and -2 were also absent in m2 / 2 mice [185,214]. One group reported impairments in sexual activity in m2 / 2 males [323] and two lines of m mutants exhibited a decrease in spontaneous locomotor activity [205,323], although no change in locomotion was reported in another m2 / 2 line [308]. There were no major changes in d and k receptor expression in m mutants [185,205,294,308], however, in some brain regions the levels of these receptors were found to be slightly lower in m2 / 2 mice [148]. Interestingly, antinociceptive effects of d agonists were reduced in m2 / 2 mice [91,123,206,307], but k-mediated antinociception was normal [91,206], implying m / d receptor interactions in analgesia. However, m2 / 2 mice were more sensitive to d agonist-mediated reversal of inflammation-induced hyperalgesia [258]. Deltorphin 2induced reward in the CPP test and withdrawal symptoms were absent in m2 / 2 mice, indicating that the rewarding effects and physical dependence of this d agonist are dependent on the m receptor [127]. Heroin and its metabolite morphine 6b-glucuronide (M6G) failed to induce analgesia in m mutants, demonstrating that the presence of the m receptor is required for antinociceptive effects of heroin [147]. Interestingly, this response was dependent on the site of disruption of the m gene since heroin and M6G analgesia was retained in m2 / 2 mice containing a disruption of exon 1 and absent in the mutants with disruption of exon 2 of the m gene [294]. Reduced anxiety behaviour in the elevated plus maze as well as a decrease in depressive-

like behaviour in the forced swim task were observed in m2 / 2 mice [85]. Ethanol self-administration was absent [267] and ethanol consumption in a free access paradigm as well as ethanol reward in the CPP test were attenuated in m2 / 2 mice [108]. Analysis of the dopaminergic system, which has been shown to interact with the opioid system, revealed that dopamine D 1 and D 2 receptor mRNA levels were slightly increased in olfactory tubercle, caudate putamen and nucleus accumbens of m mutants [247]. Two lines of mice lacking the d opioid receptor have been generated [85,355]. The levels of m and k receptor levels were unchanged and basal nociceptive thresholds were normal in d 2 / 2 mice [355]. The same study reported that spinal analgesia induced by d agonists was reduced in d mutants, however supraspinal analgesia induced by the same agents was retained. In addition, d 2 / 2 mice exhibited enhanced analgesic sensitivity to intracerebroventricular but not intrathecal administration of the non-peptide delta agonist BW373U69, suggesting the presence of another d-like system mediating d analgesia in d 2 / 2 mice. Although d 2 / 2 mice displayed normal morphine-induced analgesia, they did not develop tolerance to the analgesic effects of either morphine or the d agonist DPDPE (( DPen 2 ,D-Pen 5 )enkephalin), indicating that the d receptor is involved in opioid agonist-induced tolerance. Studies by another group found that some aspects of the behavioural phenotype of d 2 / 2 mice were opposite to those found in m2 / 2 mice [85]. For example, d 2 / 2 mice exhibited increased spontaneous locomotor activity, higher anxiety levels in both the elevated plus maze and the light / dark box as well as increased depressive-like behaviour in the forced swim test, some of which were reversed by an opioid antagonist, suggesting interactions between d and other opioid receptors. Ethanol preference in the operant self-administration and two bottle-choice paradigms was increased in d 2 / 2 mice [267]. Mice lacking the k receptor have been generated [301] and they were found to exhibit normal levels of d and m receptors [301,302]. k 2 / 2 mice displayed no changes in thermal, mechanical and inflammation-induced nociception, however they were more sensitive to chemical visceral pain [301]. The same study found that although morphine analgesia was not altered in k mutant mice, morphine withdrawal symptoms were reduced implicating the k receptor in the expression of morphine abstinence. In addition, the k agonist U-50,488H-induced effects including hypolocomotion, analgesia and place aversion were absent in k 2 / 2 mice. Recently, the generation of mice lacking all three opioid receptors has been reported [300]. Although m2 / 2 d 2 / 2 k 2 / 2 mice appear viable, their behavioural phenotype remains to be established.

2.11. OFQ /N receptor The peptide OFQ / N is similar in structure to the known

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opioid peptides but does not activate opioid receptors. OFQ / N is involved in nociception, locomotor activity, and learning and memory [263]. The receptor for OFQ / N shares high amino acid sequence similarity with m, d and k opioid receptors but does not bind typical opioid ligands. OFQ / N receptor is distributed throughout the brain and the spinal cord [216]. OFQ / N receptor-deficient mice exhibited a hearing impairment and lack of OFQ / N-induced hyperalgesia and hypoactivity [237]. Although there were no changes in morphine analgesia [237], OFQ / N-R2 / 2 mice exhibited a reduction in morphine-induced tolerance [325]. OFQ / N receptor mutants displayed improvements in memory acquirement in the water maze and memory retention in a passive avoidance task [194] as well as enhanced learning in a water-finding test, during which water-deprived mice had to locate a water source in an open field [193]. The effects mediated by OFQ / N receptor agonist Ro64-6198, including a decrease in locomotor activity and reduced motor co-ordination were absent in OFQ / N-R2 / 2 mice [118].

2.12. Serotonin receptors The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) is involved in a variety of central functions including reward, sleep, feeding, aggression and thermoregulation and imbalances in the serotonergic system have been implicated in the etiology of depression and anxiety. So far, 13 serotonin receptors have been identified and mice lacking five individual serotonin receptors have been produced [8,100]. Three independent groups have generated mice lacking the 5-HT 1A receptor. All three laboratories have reported 2/2 that 5-HT 1A mice exhibited higher levels of anxiety when measured in the open field, elevated plus / zero maze [117,249,260] and novel object tests [117]. These anxiogenic effects were more pronounced in male than in /2 female mutants [117,249,260]. 5-HT 2 mice were found 1A to display reduced depressive-like behaviour in the forced swim [249,260] and tail suspension tests [117,207]. Catecholamine depletion reversed the increase in mobility of /2 5-HT 2 mice in the forced swim test, suggesting that 1A catecholamine function was involved in the antidepressantlike response, and selective serotonin reuptake inhibitors failed to further increase the mobility time of the mutants in the tail suspension test [207]. Locomotor activity levels in the open field were found to be either normal [117,249] /2 or reduced in 5-HT 2 mice, although basal activity was 1A unchanged [260]. The anxiolytic effect of the classical benzodiazepine diazepam was absent and the sedative effects of diazepam and pentobarbital were reduced in /2 5-HT 2 mice, which could be attributed to the reduced 1A expression of GABAA receptors in amygdala and hippocampus [299]. 5-HT 1A mutants demonstrated impair-

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ments in hippocampal-dependent spatial learning as measured in the water maze and Y maze tasks although the performance in nonhippocampal memory tasks was unchanged [285]. In addition, paired pulse inhibition in the hippocampus was impaired, demonstrating abnormalities /2 in hippocampal function [285,299]. 5-HT 2 mice were 1A more sensitive to kainic acid-induced seizures, indicating enhanced limbic neuronal excitability in the mutants [285]. Serotonin and dopamine turnover rates were increased in /2 some brain regions of 5-HT 2 mice, indicating changes 1A in monoamine metabolism [5]. An in vivo microdialysis study found that 5-HT 1A receptor mutants displayed higher basal serotonin levels in the frontal cortex and hippocampus, which were further increased upon exposure to an open field or the selective serotonin reuptake inhibitor fluoxetine [250]. However, other studies reported no changes in basal serotonin levels in striatum and hippocampus and greater increase in fluoxetine-induced /2 serotonin levels in striatum of 5-HT 2 mice, demon1A strating the absence of 5-HT 1A autoreceptor function [114,151]. 5-HT 1B agonist-mediated decrease in striatal serotonin release and the effect of a 5-HT 1B antagonist on fluoxetine-induced serotonin release were potentiated in 5-HT 1A mutants, suggesting enhanced 5-HT 1B autorecep/2 tor function [150]. Some brain regions of 5-HT 2 mice 1A were found to exhibit lower serotonin transporter levels which could contribute to the changes in serotonergic neurotransmission in the mutants [6]. Mice deficient in the 5-HT 1B receptor have been generated [286] and they were reported to show increased aggressiveness in both males and females, enhanced impulsive behaviour and reactivity to unpredictable stimuli [21,27,261,286]. The increase in locomotor activity induced by the 5-HT 1A / 1B agonist RU24969 was absent in 5-HT 1B mutants, implicating the 5-HT 1B receptor in this 2/2 effect [192,261,286]. 5-HT 1B mice displayed higher exploratory activity in a novel object task and better performance in the water maze indicating enhanced spatial learning [192]. A sleep–wakefulness study found that 5HT 1B mutants exhibited increased paradoxical sleep, decreased slow-wave sleep and lack of paradoxical sleep rebound following sleep deprivation, suggesting a role for /2 the 5-HT 1B receptor in regulation of sleep [20]. 5-HT 2 1B mice exhibited increased ethanol consumption in a free access paradigm and developed higher ethanol-induced ataxia [54]. In addition, cocaine-induced locomotor and reinforcing properties during operant responding as well as cocaine-induced expression of the truncated form of FosB, /2 DFosB were increased in 5-HT 2 mutants [268,269]. 1B However, other studies found that ethanol-seeking behaviour was normal and that both ethanol and cocaine/2 induced CPP were absent in 5-HT 2 mice [12,22,265]. In 1B addition, cocaine and RU24696-induced c-fos expression was reduced in the brains of 5-HT 1B mutants [187]. The locomotor-stimulant effects of MDMA (3,4-methylenedioxy-N-methamphetamine) or ‘ecstasy’ were reduced

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/2 in 5-HT 2 mice [288]. Prepulse inhibition was elevated, 1B startle reactivity was reduced and the effects of RU24969 on prepulse inhibition and startle response habituation /2 were absent in 5-HT 2 mice, indicating changes in 1B sensorimotor gating in response to 5-HT 1B inactivation [72,73]. In another study, however, only a decrease in startle reactivity but no changes in prepulse inhibition and habituation were observed in 5-HT 1B mutants [66]. 8-OHDPAT, a 5-HT 1A receptor agonist had a higher efficacy in inducing hypothermia in 5-HT 1B mutants than in wild-type mice [95]. 5-HT 1B and 5-HT 1B / 1D agonist-induced inhibi/2 tion of serotonin release was absent in 5-HT 2 mice both 1B in vitro [256] and in vivo [324], demonstrating loss of 5-HT 1B autoreceptor function. In addition, in response to selective serotonin reuptake inhibitors, 5-HT 1B receptor mutants exhibited higher induction of extracellular serotonin levels in hippocampus [151,190] and an increased behavioural sensitivity [207]. Serotonin and dopamine levels were lower in some brain regions [5] and serotonin transporter density was found to be reduced in the neostriatum and increased in the amygdala and hip/2 pocampus of 5-HT 2 mice [6]. The increase in transpor1B ter density was accompanied by increases in serotonin innervation. 5-HT 1A agonist-mediated decrease in hip2/2 pocampal serotonin levels was attenuated in 5-HT 1B mice, suggesting a decrease in 5-HT 1A autoreceptor function [150]. Mice lacking the 5-HT 2C receptor exhibited spontaneous epileptic seizures, lower seizure threshold in response to a GABAA antagonist and faster progression of seizure activity implicating 5-HT 2C in inhibition of neuronal 2/2 excitability [319]. In addition, 5-HT 2C mice had higher body weights and fat stores as a result of hyperphagia, suggesting that this receptor may be involved in the control of food intake. 5-HT 5A receptor-deficient mice displayed increased exploratory activity in the open field and novel object tests, although no changes in anxiety-like behaviour were observed [104]. The same study also reported that the locomotor-stimulant effects of D-lysergic acid diethylamide /2 (LSD) were attenuated in 5-HT 2 mice indicating that 5A the 5-HT 5A receptor is involved in the LSD-induced exploratory activity.

3. Advantages and limitations of GPCR gene knockout models GPCRs in the CNS are important targets for drug therapy. Natural mutations leading to alterations or loss of GPCR function have been identified in several species including humans. Some well-known examples include the numerous mutations of the vasopressin V2 receptor resulting in nephrogenic diabetes insipidus, a point mutation of the thromboxane A 2 receptor leading to a bleeding

disorder and mutations of the melanocortin MC 4 receptor resulting in obesity [277]. However, only a few examples of natural GPCR knockout animal models are available such as the orexin receptor 2 inactivation in the canine that leads to a narcolepsy phenotype [179] and the absence of melatonin 1b receptor in the Siberian hamster [333]. Hence, the gene inactivation technology has allowed researchers to generate mouse models of altered sensorimotor function, hyperactivity, anxiety, aggression, analgesia, obesity and drug abuse. Studies on the effects of inactivation of one or more members of a GPCR subfamily in addition to the deletion of their endogenous ligands have contributed to the existing knowledge about the physiological functions of receptor systems. There is abundant evidence for synergistic or opposite interactions between different GPCRs and between receptors and other proteins in mediating behavioural function. Since by deleting a GPCR from the mouse genome, the expression, function and pharmacology of other receptors may be affected, mouse knockout models can be used to investigate such interactions. In addition, gene inactivation permits the study of specific functions of receptor subtypes which in many cases has been hindered by the lack of receptor selective ligands. Inactivation of the orphan GPCR genes for which the endogenous ligands remain elusive may also be used as an important tool in elucidating their physiological roles. However, the use of gene knockout mice, especially in behavioural research has some limitations. One of the major disadvantages is the fact that most of these mouse models have a mixed genetic background originating from the acceptor or ‘host’ strain and the ‘donor’ strain, from which the ES cells used in the gene targeting have been isolated. Since different mouse strains have been shown to perform differently on several behavioural tests [120,217,290], it is possible that the phenotypic changes observed in the mutant mice are a result of variations in the mixed genotype and not the actual gene deletion [99,254]. In fact, some studies have reported that the background genotype of the donor strain was responsible for at least some of the phenotypic traits observed in GPCR knockout mice [141,197]. Several measures can be taken in order to avoid potential influence of the donor strain genes on the mutant phenotype. Firstly, mutant mice on a mixed donor / host genetic background can be backcrossed to the host strain for many generations to dilute the presence of the donor genes. This method has been used widely and congenic mutant strains that have been backcrossed for five or more times into the host strain have become the standard in many knockout studies. Secondly, the ES cells carrying the desired mutation can be implanted into blastocysts isolated from females from the same mouse strain, giving rise to mutant mice with a pure genetic background. Other possible complications in using the mouse knockout model in behavioural research have been encountered

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in a few cases in which the findings of one laboratory were not replicated by others [55]. The variations in results could be attributed to factors including environmental differences and modifications in test protocols. Researchers must therefore clearly state the detailed methodology, conditions and type of behaviour tested in their studies. In addition, the availability of several tests to assess one type of behaviour [57,58] should provide more complete information about the changes in a particular phenotype of a mouse knockout line. It has been well established that GPCRs form homo- and heterooligomeric complexes in the cell and that oligomerization can influence receptor pharmacology and function [173,176]. Therefore it is conceivable that the behavioural phenotype of knockout mice could also be affected by the loss or changes in heterooligomeric receptor complexes. The absence of one receptor type can disrupt heterooligomeric structures thus leading to altered function of other receptors. Finally, the in utero inactivation of a GPCR may result in embryonic death or developmental abnormalities if the receptor is important in embryonic and postnatal development. According to Table 1, the inactivation of nine individual GPCR genes has resulted in significant or total embryonic or neonatal lethality. However, most single and multiple GPCR knockout mice are viable which allows investigators to study changes in behavioural phenotypes in detail. GPCR deletion may also lead to adaptive or compensatory changes. Analysis of the expression of other members of the receptor family and other proteins known to interact with the deleted receptor can be the first step in assessing the presence of adaptive changes in the mutant mice. The inducible or conditional gene knockout strategies can also be used if conventional gene inactivation leads to embryonic or postnatal lethality. Two examples are the Cre /loxP recombination system, which uses Cre recombinase and its two loxP recognition sites flanking the target gene to control its expression [225,287] as well as the inducible bacterial system in which the induction of gene expression is controlled by a bacterial transcription factor [298]. These techniques allow the generation of knockout animals with gene deletions under either spatial or temporal control. Recent examples of the use of these alternative gene disruption methods include the conditional knockout of the NPY Y 2 receptor using the Cre /loxP system [278] and the inducible knockout of the serotonin 1A receptor using the bacterial tetracycline system [105]. Although these strategies represent a promising tool to generate and study gene knockout mice without the complications of embryonic lethality or potential compensatory changes, they have some limitations. These include the requirements for high Cre expression and several transgenic lines to obtain a mouse with the desired expression pattern in the case of the Cre /loxP system as well as the need for constant administration of the antibiotic tetracycline or its

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derivatives to abolish gene expression when using the inducible bacterial system.

4. Conclusions Over 80 single, several double and one triple GPCR mouse knockout models have been generated and characterized in the past decade. Undoubtedly, more GPCR genes will continue to be inactivated in the mouse in order to further assess their functions. These knockout lines have become an indispensable tool in biological research and the availability of rodent models of behaviour has enabled the analysis of the role of GPCRs in CNS function. As described in this review, extensive studies using genetically modified mice have provided new insight into central GPCR function as well as into mechanisms of behaviours including motor control, learning and memory, reward, depression, anxiety and aggressiveness at the molecular and cellular levels.

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